Next Article in Journal
Interruptin C, a Radioprotective Agent, Derived from Cyclosorus terminans Protect Normal Breast MCF-10A and Human Keratinocyte HaCaT Cells against Radiation-Induced Damage
Next Article in Special Issue
The Attenuating Effect of Beta-Carotene on Streptozotocin Induced Diabetic Vascular Dementia Symptoms in Rats
Previous Article in Journal
Visible Light-Driven Alkyne-Grafted Ethylene-Bridged Azobenzene Chromophores for Photothermal Utilization
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 10
10.3390/molecules27103297
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols

by
Arslan Iftikhar
1,
Rimsha Nausheen
1,
Humaira Muzaffar
1,
Muhammad Ahsan Naeem
2,
Muhammad Farooq
3,
Mohsin Khurshid
4,
Ahmad Almatroudi
5,
Faris Alrumaihi
5,
Khaled S. Allemailem
5,* and
Haseeb Anwar
1,*
1
Department of Physiology, Government College University Faisalabad, Faisalabad 38000, Pakistan
2
Department of Basic Sciences, KBCMA College of Veterinary and Animal Sciences, Narowal 51600, Pakistan
3
Department of Clinical Sciences, College of Veterinary and Animal Sciences, Jhang 35200, Pakistan
4
Department of Microbiology, Government College University Faisalabad, Faisalabad 38000, Pakistan
5
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(10), 3297; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27103297
Submission received: 17 April 2022 / Revised: 16 May 2022 / Accepted: 18 May 2022 / Published: 20 May 2022
(This article belongs to the Special Issue Pharmacology of Natural Product)
Browse Figure
Versions Notes

Abstract

:
Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of diverse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.

1. Introduction

Honey is the primary product of apiculture with a history of use corresponding to the history of mankind. The nutritional and therapeutic benefits of honey have been indicated in every culture and religion of the world including Greek, Roman, Christianity, and Islam [1,2]. Physicians of ancient times have extensively discussed the medicinal qualities of honey. Ancient Egyptian physicians employed honey in their medication 5000 years ago and the prehistoric Greeks believed honey beneficial for vigor and longevity. The first written reference to the beneficial effects of honey, a Sumerian tablet writing, dating back to 2100–2000 B.C., indicates honey as a potential drug to be used against various complaints. Ibn e Sina, also known as Avicenna in the west, employed honey as a remedy for tuberculosis [3,4]. Ancient Egyptian physicians used to prescribe a mixture of honey, grease, and fiber for wound healing. It also held a high rank in Chinese medicine and was used for wound healing and various gut diseases. Hippocrates, the Greek physician also known as the Father of Medicine, endorsed the use of a mixture of honey and water (hydromel) for quenching thirst. He also recommended the combined use of honey and vinegar (oxymel) for relieving pain. Many other eminent personnel including Aristotle, Aristoxenus, Porphyry, Cornelius Celsus, and Dioscorides were also convinced of the beneficial effects of different kinds of honey in various illnesses [5,6].
Honey has also been indicated as a potential remedy for various ailments in almost all prevailing religions. In the bible, the word ‘honey’ has been mentioned about 61 times and there are at least six verses that suggest the beneficial effects of honey (Exodus 3:6–8; Samuel 14:24–27; Genesis 43:11; Proverbs 24:13; Matthew 3:1–4; Revelation 10:7–11). In Islam, both the Quran and Hadiths (Prophetic traditions) refer to honey as a source of healing in various diseases (Al-Quran 16:68–69; Sunan Ibn Majah 32:3578). The prophet Muhammad recommended honey for various purposes, including for the treatment of ailments related to the digestive system (Sahih Muslim 39:5770), heart (Sahih al-Bukhari 76:12), and healing phenomenon (Sahih al-Bukhari 76:4). The Almighty’s divine claim about this wonderful liquid gold not only advocates the use of honey for the prevention and treatment of various disorders, but also instigates the eagerness to explore more scientific rationalization for its unrevealed and mysterious beneficial effects.

2. Composition of Honey

The beneficial effects of honey are attributed to various biological bioactive components. The presence of these active compounds justifies the substantial biological benefits of honey. The percentage of all these components varies among different types of honey. In general, honey consists of more than 200 substances. It is mainly a carbohydrate product, and sugars constitute more than 90% of solids. Main sugars found in honey include glucose, sucrose, maltose, fructose, melezitose, isomaltose, maltulose, turanose, nigerose, melibiose, panose, and maltotriose. Water is the second most important component of honey. Conjointly with carbohydrates and water, honey also contains enzymes, vitamins, minerals, flavonoids, and polyphenols [7,8,9]. Riboflavin (Vit. B2), Niacin (Vit. B3), Pantothenic acid (Vit. B5), Pyridoxine (Vit. B6), Folate (Vit. B9), and vitamin C are the major vitamins found in honey. Among minerals, potassium is the major one while calcium, magnesium, sodium, sulfur, and phosphorus are also found in a significant amount. The main enzymes found in honey include invertase (saccharase), diastase (amylase), and glucose oxidase. Non-enzymatic proteins, including glycoprotein, MRJP1, and apalbumin-1, are also found in honey, but in very minute quantities [9].
Polyphenols are a major class of naturally occurring organic compounds that are defined by multiples of phenol units. Polyphenols consist of flavonoids and nonflavonoids that are separated into subclasses based on the number of phenol units, substituent groups, and/or the kind of linkage between phenol units in their molecular structure. A 15-carbon (C6–C3–C6) backbone with two phenyl units (A and B), along with a heterocyclic unit (C), is the characteristic of flavonoids. Non-flavonoid polyphenolic compounds include phenolic acids, coumarins, lignans, hydrolyzable tannins, lignins, and condensed tannins. Honey contains a wide range of both flavonoids and phenolic acids [10].
Among flavonoids, quercetin, myricetin, kaempferol, luteolin, rutin, naringenin, naringin, chrysin, rhamnetin, isorhamnetin, apigenin, pinocembrin, pinobanksin, galangin, tricetin, catechin, and hesperidin are the major compounds found in various varieties of honey. The most common phenolic acids, occurring in almost every honey type, include caffeic acid, gallic acid, coumaric acid, syringic acid, cinnamic acid, ferulic acid, chlorogenic acid, ellagic acid, benzoic acid, vanillic acid, phenylacetic acid, and homogentisic acid. In honey, though polyphenols are among the minor components, they are the main explanation for various health benefits honey. Several in vitro and in vivo studies have demonstrated the beneficial effects of these flavonoids and non-flavonoids in various diseases and maladies [11,12,13,14]. Since the taste, color, and composition of various kinds of honey depend upon the type of floral origin, the geographical area, and the various species of bees engaged in honey production, the qualitative and quantitative differences in the polyphenolic contents of various types of honey have been determined in various studies that may explain the diverse pharmaceutical properties of these different types of honey (Table 1).

3. Medicinal Properties of Honey

In addition to its nutritive value, honey possesses a wide variety of therapeutic properties. It has been used to treat several diseases since ancient times [25,26]. Its most common application is for healing wounds and skin infections [27,28,29]. Honey possesses significant antibacterial [30,31,32], antiviral [33,34], antifungal [27,35,36,37], antioxidant [27,38,39,40], anti-inflammatory [41,42,43], antineoplastic [28,44], antimicrobial [45,46,47], anticarcinogen [48,49,50], antiarrhythmic [51,52], antileishmanial [53,54], antithrombotic, antiplatelet [55,56], antimutagenic [57,58], antinociceptive [59,60], antimycobacterial [7,61], antiproliferative [62,63], and immune-boosting [64,65,66] properties. It is also shown to have hypocholesterolemic [67,68], cardioprotective [69,70], antihypertensive [71], hepatoprotective [72,73], gastroprotective [41,74], neuroprotective [75,76], nephroprotective [77,78], and hypoglycemic [79,80] effects. The literature suggests that honey is quite useful to overcome complications of the reproductive system in both males and females. It is shown to improve spermatogenesis [81] and improve sperm count and their motility [82]. It is shown to protects against vaginal and uterine atrophy [83] and improves the normal estrus cycle [84].

4. Honey and Neurological Disorders

Neurological disorders are ailments of the central and peripheral nervous systems. Neurological disorders have become one of the major health issues, particularly in the recent modern era. The burden of neurological disorders has increased dramatically in the last few decades throughout the world, from third-world countries to the world’s most developed countries [85]. Among neurological disorders, neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), and stroke are the most commonly prevalent maladies. By and large, the dysfunction or death of nerve cells in specific areas of the brain is the main cause of all these diseases.
The leading underlying cause of nerve death is oxidative stress caused by an accumulation of free radicals and depletion of antioxidants [86]. Increasing the levels of antioxidants can be beneficial against these neurodegenerative diseases [24]. Honey contains antioxidants in the form of polyphenols and flavonoids. All kinds of honey contain these bioactive compounds but in varying concentrations. Various colorimetric assays reveal that the total phenolic content in various types of honey varies from 86 mg/kg to 1141 mg/kg [87], whereas the range for the flavonoid content is from 36 mg/kg to 150 mg/kg of honey [88]. Both flavonoids and polyphenols protect neurons against oxidative damage, improve neuronal function and enhance regeneration, protect neurons from neurotoxicity, and modulate neuronal signaling pathways [24].
The most common flavonoids and polyphenols present in almost all types of honey that are found to be beneficial against neurodegenerative diseases include apigenin, benzoic acid, caffeic acid, catechin, chlorogenic acid, chrysin, cinnamic acid, coumaric acid, ellagic acid, ferulic acids, galangin, gallic acid, hesperetin, isorhamnetin, kaempferol, luteolin, myricetin, naringenin, quercetin, and syringic acid [88] (Figure 1).
Though plenty of research is available in the literature archive advocating the potential role of honey in ameliorating neurological disorders, the polyphenols components of honey proclaim way more potential roles of sweet nectar. In this review, we have indexed and comprehended the role of various polyphenols that are found in honey with their reported and potential role in the prevention, management, and treatment of various neurological disorders (Table 2).

4.1. Alzheimer’s Disease

Alzheimer’s disease (AD) is a very common age-related neurodegenerative disease. The pathology of the disease includes the formation of neuritic plaques, mainly composed of the β-amyloid (Aβ) peptide, along with neurofibrillary tangles [185,186]. Studies suggest oxidative stress as the underlying cause of these neuronal malfunctions in AD [187,188]. Membranes of brain cells are highly sensitive to oxidative damage because of high levels of polyunsaturated fatty acids [189,190]. The excessive production of reactive oxygen species causes mitochondrial damage and decreased ATP production in AD. Many preclinical investigations suggest that oxidative stress causes neuroinflammation and stimulates Aβ production. Neuronal cell dysfunction and death are the ultimate results of these processes [97,191]. In the literature, honey has been reported to protect the astrocytes from this oxidative damage. Astrocytes serve as the major site for the expression of genes causative of Alzheimer’s disease [192,193].
Different varieties of honey have been reported to act as a potential natural source of acetylcholinesterase (AChE) inhibitors in Alzheimer’s disease. Acetylcholinesterase activity is associated with a depletion of acetylcholine which results in memory-related problems in Alzheimer’s disease. Therefore, the inhibition of acetylcholinesterase (AChE) is a possible therapeutic strategy to deal with this disorder [194,195]. The co-administration of honey syrup and an aqueous saffron extract is shown to increase the level of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and mitigate oxidative stress in aluminum chloride-induced neurotoxicity. Aluminum is an environmental factor that is reported to alter several oxidative enzymes and other biomolecules related to neurotoxicity and Alzheimer’s disease (AD) [196]. Another hallmark of Alzheimer’s disease is the loss of cortical and hippocampal neurons due to reduced cerebral blood flow, which consequently leads to cognitive impairments. A study by Saxena et al. revealed that the daily supplementation of Tualang honey to chronic cerebral hypoperfusion induced by permanent bilateral common carotid arteries ligation (2VO) in rats efficiently reduced neuronal cell loss and increased the viable neurons [197]. In addition to honey as a whole, several studies have been registered in the literature archive regarding the potential beneficial effects of specific components of honey in AD patients.
Quercetin is well known to improve the mitochondrial activity in living cells [89]. Pre-treatment with quercetin decreases oxidative stress by the activation of the Nrf2 signaling pathway in β-Amyloid-induced models of Alzheimer’s disease [90]. Nrf2 signaling is involved in balancing the levels of antioxidant enzymes, and its activation serves as the marker for the amelioration of neurodegeneration in AD models [198,199,200,201]. Furthermore, quercetin also shows a neuroprotective effect in AD models via the regulation of PON2 activity [91]. The PON2 protein, a member of the paraoxonase family, is involved in reducing oxidative stress. Being localized mainly in mitochondria, PON2 decreases oxidative stress by preventing the formation of superoxide, a free radical, at the inner mitochondrial membrane [202]. Quercetin has also been reported to cause a reduction in neuroinflammation and neurodegeneration, a decrease in astrogliosis, and recovery in cognition disabilities in mouse models of AD [92,93].
Myricetin, a flavonoid present in honey, has been shown to have a protective effect on neurons present in the hippocampus, a part of the brain involved in memory processes. Myricetin reverses the impairments of cognitive functions and improves the memory in streptozotocin-induced models of AD [94]. It is reported to exhibit an anti-tau protein effect and preventive effect against the formation of amyloid-beta aggregates in AD [95]. In addition to that, myricetin reduces the activity of acetylcholinesterase as well as increases the concentration of acetylcholine in the hippocampus. Treatment with myricetin ameliorates the damage caused by oxidative stress in the hippocampal region of mice. It does so by increasing the levels of antioxidative enzymes [96]. Myricetin also indicates anti-inflammatory activity via the inhibition of the NF-κB pathway and NLRP3 inflammasome [97,98]. The formation of amyloid-beta fibrils is an important hallmark of AD. Myricetin inhibits not only the formation of fibrils of amyloid-beta, but also the oligomers of amyloid-beta [99].
Kaempferol, another flavonoid present in honey, has also been reported to improve the cognitive deficits in the drosophila model of AD. Beg and colleagues reported that kaempferol can inhibit the formation of senile plaques which are characteristics of AD. It decreases the level of lipid peroxidation in drosophila which increased due to AD. Kaempferol also protects the cell from oxidative and apoptotic damage [100]. Furthermore, it has also been demonstrated that kaempferol mitigates cognitive dysfunctions by controlling oxidative damage and neuroinflammation in a model of sporadic dementia. It regulates the concentrations of antioxidative enzymes, such as superoxide dismutase (SOD), and causes a reduction in the levels of tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine [101]. Kaempferol has also been reported to impart a neuroprotective effect against AD via anti-apoptotic activity as well. It causes the downregulation of genes associated with apoptosis, such as Bcl-2-associated X protein (Bax) and cleaved caspase-9 in SH-SY5Y neuronal cells treated with amyloid-beta (Aβ) [102]. It has been observed that the density of neurons decreases in the CA1 region of the hippocampus of streptozotocin-induced rat models of AD. However, in treatment with kaempferol, an elevation in the density of neurons is seen in the same region [103]. Kaempferol has also been reported to downregulate the expression of proteins that are associated with inflammation, such as interleukin-1β (IL-1 β), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2), in amyloid beta-induced models [104]. Kaempferol reduces the level of intracellular oxidative stress and protects the cell from damage [105].
Luteolin, another antioxidant, possesses a strong potential against Alzheimer’s disease. This potential is attributed to its capacity to inhibit the formation of amyloid-beta and tau protein aggregates. It causes the downregulation of various inflammation- and apoptosis-associated proteins such as tumor necrosis factor α (TNF-α), cyclooxygenase 2 (COX-2), and interleukins. It ameliorates oxidative stress by scavenging the free radicals. Luteolin also modifies the functions of various transcription factors such as NF-Kb, p53, cJun, p53, Nrf-1, β-catenin, and AP-1 [106]. Luteolin improves deficits of memory and averts the decrease in density of the cell layer in the CA1 hippocampal region of streptozotocin-induced AD models [107]. Galangin, a flavanol component of honey, diminishes the cytotoxicity induced by okadaic acid in PC12 cells. It decreases the levels of p-tau, β-secretase, and Aβ42. Galangin diminishes autophagy by increasing the phosphorylation of Akt and mTOR and ameliorating the phosphorylation of GSK3β. Both factors contribute to the inhibition of autophagy in okadaic acid (OA)-induced PC12 cells [108]. Galangin has also been demonstrated to improve cognitive and memory functions as well as increase the concentration of acetylcholine in scopolamine-induced memory impairment models [109].
Caffeic acid, a phenolic acid present in honey in significant amounts, reduces inflammation, the activity of acetylcholinesterase, and oxidative stress in models of AD. It regulates the expression of p53, MAPK, p38, and caspase 3. These anti-oxidative and anti-inflammatory properties of caffeic acid make it suitable for use against AD [110]. Cinnamic acid, another bioflavonoid present in honey, is shown to attenuate the formation of amyloid plaques and to improve the memory impairments in 5XFAD mice through lysosomal biogenesis via the activation of peroxisome proliferator activating receptor α (PPARα), a member of the nuclear receptors’ family [111].

4.2. Parkinson’s Disease

Parkinson’s disease (PD) is the second most widespread and chronic neurological disorder in the present world. It is a neurodegenerative disease, mainly characterized by the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNc), a part of the midbrain. This degeneration happens mainly because of the formation of Lewy bodies. Lewy bodies are cytoplasmic inclusions of misfolded proteins, primarily the α-synuclein, along with ubiquitin and others. Rigidity, tremor, bradykinesia, postural instability, and gait problems are the basic clinical features attributed to PD. Non-motor symptoms associated with PD include sleep difficulty, depression, and deficits of olfaction. The death of neuronal cells in PD is mediated by many factors which include oxidative stress, endoplasmic stress, dysfunction of mitochondria, defects in the process of autophagy, and inflammation. Oxidative stress results from the accumulation of reactive oxygen species (ROS) and a lack of antioxidants [203,204,205,206,207,208,209,210]. Since this oxidative stress is the key player behind neurodegeneration, the use of antioxidants is a common therapeutic strategy against PD [211].
Honey contains a variety of antioxidants in the form of flavonoids and phenolic acids, which can potentially reduce oxidative stress and repair the damage caused by it. Honey, along with other apitherapeutic products, has been reported to inhibit the activity of monoamine oxidase (MAO), which is involved in reducing the free radical scavenging activity and causing oxidative damage in neurodegenerative disorders such as Parkinson’s disease [212]. Recently a study by Topal et al. reported that Parkinson’s patients can make use of only pollen and honey produced by those bees that feed on flowers of Vicia faba L. as a treatment for Parkinson’s disease. This kind of honey contains a considerable percentage of L-DOPA, a commonly employed drug against Parkinson’s [213]. In conjunction with these studies, the polyphenols present in honey are also well studied individually for their use against neurodegenerative diseases.
Quercetin, a flavonoid present in almost all kinds of honey, has been reported to protect neuronal degeneration in substantia nigra and increase dopamine levels in MitoPark mice. It also initiates the activation of various kinases such as PDK1 and Akt which are important for the survival of neuronal cells. Further, it enhances the expression of BDNF, ameliorates mitochondrial dysfunction, and upsurges the energy production by the mitochondria [112]. Quercetin causes the restoration of activities of antioxidant enzymes and repairs the cognition deficits related to PD in the 6-hydroxydopamine-induced model of Parkinson’s disease [113]. El-horany et al. demonstrated that quercetin shows a neuroprotective effect in the rotenone-induced rat model of Parkinson’s disease via decreasing the endoplasmic reticulum stress and boosting the process of autophagy. It does so by decreasing the C/EBP homologous protein (CHOP) which is related to ER stress and increasing the expression of Beclin-1, which activates autophagy [114]. Myricetin, another flavonoid, is also considered very beneficial against Parkinson’s disease. It is reported to not only increase the levels of dopamine in a dose-dependent manner, but also prevent the degeneration of dopaminergic neurons in the transgenic drosophila model of Parkinson’s disease [115]. A study on LPS-induced models of PD reveals that myricetin employs considerable neuroprotection in dopaminergic neurons via the inhibition of inflammation. It ameliorates the changes in motor behaviors caused by PD and prevents the loss of neurons by preventing the activation of microglia. It also diminishes the activation of inflammation-associated cytokines (IL-1 β, TNFα, and IL-6) and some signaling pathways such as MAPK and NF-Κb [116].
Chrysin, a flavonoid abundantly present in honey, is well studied for its role in PD. Chrysin has been reported to exhibit a neuroprotective effect against the MPTP-induced loss of dopaminergic neurons in mice by increasing the expression of the survival factor MEF2D via the AKT/GSK3β/MEF2D pathway. It also causes the inhibition of MAO-B [117]. Chrysin is found to ameliorate the oxidative damage, neuroinflammation, and dysfunction of Na+, K+-ATPase activity in the 6-hydroxydopamine mice model of Parkinson’s disease [118]. Chrysin improves the condition of neuron loss and alterations in motor functions along with improved memory processes in rotenone-induced rat models of PD [119].
Ellagic acid, another polyphenol, is shown to exert an inhibitory effect on monoamine oxidase (MAO) activity which results in decreased oxidative stress and prevents the loss of dopaminergic neurons [120]. Sarkaki et al. advocated the use of ellagic acid against PD as it protects neurons from oxidative damage induced by 6-OHDA via modulating the levels of antioxidants [121]. A study on ellagic acid revealed that ellagic acid causes the extenuation of apoptosis and reduces oxidative stress by enhancing the antioxidant defense system in the 6-OHDA-induced model of Parkinson’s disease. Additionally, it also causes the inhibition of MAO-B and modulates the ERβ/Nrf2/HO-1 signaling cascade. Altogether, these findings support the potential neuroprotective role of ellagic acid in PD patients [122].
Cinnamic acid, another bioflavonoid present in honey, is known to be effective against PD in the MPTP-induced model. It protects neurodegeneration in substantia nigra via the activation of peroxisome proliferator activating receptor α (PPARα), which exerts a neuroprotective role in multiple ways [123]. Galangin, the flavonol class member, is reported to prevent the loss of dopaminergic neurons in LPS-intoxicated mice. It inhibits microglial activation via AKT, NF-κB p65, JNK, and p-38 signaling association and suppresses the formation of inflammation-related factors [124]. Choi et al. demonstrated that galangin is an anti-inflammatory agent in microglia stimulated by LPS. It causes the activation of PPAR-γ, which is shown to be neuroprotective in PD through mitigating inflammation, mitochondrial dysfunction, the inhibition of apoptosis, and oxidative stress [125,126,127]. Apigenin, another component of honey, has been described to be a neuroprotective agent against PD in the transgenic Drosophila model. Its neuroprotective role is attributed either to its antioxidative property through the inhibition of MAO, or anti-apoptotic activity via the inhibition of caspase-3 activation [128].

4.3. Huntington’s Disease

Huntington’s disease (HD) is another genetic, progressive neurodegenerative disease prevalent all around the globe. The main cause of the disease is the repeated expansion of the CAG trinucleotide in the huntingtin gene (HTT) present on chromosome 4. It leads to the production of the mutant huntingtin protein (mHTT) which contains an abnormally long tract of polyglutamine [214,215,216]. The penetrance of the disease increases with age and is transferred to the next generation in an autosomal dominant manner. Symptoms of this disease include a decline in motor functions, cognitive dysfunctions, and psychological disturbances, which include both neural dysfunction and, ultimately, cell death. These neurodegenerative changes initially began in the striatum and gradually spread to other areas such as the hippocampus and cortex [130,217]. Oxidative stress is considered the key player in the occurrence and progression of the disease [130,218]. Due to the involvement of oxidative stress, the use of antioxidants is believed to be highly beneficial against HD. Like other neurodegenerative diseases, antioxidants present in honey have been extensively investigated in several studies for their potential benefits in HD.
Quercetin is shown to be involved in the protection of neurons in a 3-NP-induced model of HD. It causes a decrease in oxidative stress by modulating antioxidant systems. It also elevates the energy production of mitochondria via the regulation of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) or sirtuins (SIRT1). Additionally, it has also been found helpful in the improvement of motor functions of neurons [129]. Quercetin is reported to ameliorate the neurochemical, neuropathological, and behavioral malfunctions induced by 3-nitropropionic in rats. It causes the suppression of monoamine oxidase A (MAO-A) activity, which exerts an overall anxiolytic effect [130]. Another important flavonoid, myricetin, along the same lines, has been described to be neuroprotective against HD. Myricetin reduces the aggregation of polyglutamine in HD patients [131]. It decreases the proteo-toxicity caused by polyglutamine aggregates and repairs the behavioral impairments in 3-NP-induced models of HD [132].
Chrysin shows antioxidant and anti-apoptotic activity in the 3-NP-induced model of HD. It causes an increase in the levels of antioxidant enzymes. It also causes the downregulation of pro-apoptotic factors such as Bax, along with the upregulation of anti-apoptotic factor Bcl-2 [133]. A recent study by Haider et al. demonstrates that chrysin shows a neuroprotective effect against the 3-NP-induced model of HD. It causes the restoration of neurobehavioral functions and modulates motor functions through increasing serotonin levels and monoamine oxidase (MAO) activity. Furthermore, it has also been reported to protect the degeneration of striatal neurons [134]. On the other hand, another important component of honey, chlorogenic acid, has also been reported to protect the cells from toxicity and genotoxicity induced by 3-NP [135].

4.4. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is another neurodegenerative disease that adversely affects the nerve cells in the brain and spinal cord, resulting in a loss of muscle control. It is an adult-onset, fatal, paralytic, and progressive degenerative disease, primarily of motor neurons. It involves the formation of intracellular aggregates of the TAR DNA-binding protein 43 (TDP-43) protein. Expansions of a hexanucleotide repeat in C9orf72 serve as the main genetic source of ALS. It can be either inherited, known as familial amyotrophic lateral sclerosis, or sporadic. The formation of aggregates of enzyme Cu-Zn superoxide dismutase (SOD) is a common feature of both forms. It begins initially with focal weakness, but spreads persistently to most muscles, together with the diaphragm. Almost half of the patients with ALS switch to develop behavioral and cognitive dysfunction [138,219,220,221]. Neurodegeneration in ALS is mainly attributed to oxidative stress and, therefore, antioxidant therapy may help fight against the disease [222].
Another major hallmark in the early onset of amyotrophic lateral sclerosis is the mutations in the gene encoding ubiquitin chaperone Ubiquilin 2 (UBQLN2), which causes defects in ubiquitin-binding abilities and results in the restricted delivery of ubiquitinated substrates to proteasomes for degradation [223]. A study by Phokasem et al. revealed that coffee honey restored locomotor capacity, increased learning ability, and mitigated oxidative stress in the brain of the Ubiquilin-knockdown Drosophila model [224].
Quercetin, an important flavonoid component of honey, is evaluated for its neuroprotective effect against ALS. Derivatives of quercetin were shown to have an inhibitory effect on the aggregation of the Cu-Zn superoxide dismutase (SOD) enzyme [136]. Recently, quercetin itself has been studied for its role in ALS. It is shown to inhibit the aggregation of the Cu-Zn superoxide dismutase (SOD) enzyme. It binds to monomeric and oligomeric forms of the SOD enzyme, thus preventing self-association as well as the elongation of fibrils of the SOD enzyme [137]. Kaempferol, another flavonoid, shows protection against neurotoxicity induced by mutant SOD1 in a model of ALS. Kaempferol prevents cell death and reduces the aggregation of intracellular SOD1. It boosts up the process of autophagy, a way of eliminating misfolded protein aggregates, via the AMP-activated protein kinase (AMPK)-mTOR pathway. It increases AMPK phosphorylation which inhibits mTOR phosphorylation, and subsequently induces autophagy [138,139].
Coumaric acid is another important component of honey that is shown to be beneficial against ALS. It is shown that p-coumaric acid exerts a neuroprotective effect against mutant SOD1-induced neurotoxicity. It ameliorates oxidative stress and endoplasmic reticulum stress. It also enhances the process of autophagy [140]. Gallic acid has also been suggested to be effective against sporadic amyotrophic lateral sclerosis. It boosts up the activities of antioxidant enzymes and, at the same time, decreases lipid peroxidation levels. It declines the process of inflammation via the downregulation of inflammation-related factors such as TNF-α, IL-6, IL-β, and NF-κB in the quinolinic acid-induced neurotoxicity model [141]. Gallic acid is shown to improve motor functions and motor learning abilities in a dose-dependent manner in the aluminum-induced neurodegeneration model. It prevents glutamate excitotoxicity and maintains antioxidant status. It inhibits the formation of neurofibrillary tangles, thus protecting neurons from damage [142]. Another study by Aaron and colleagues has also suggested gallic acid to be beneficial against ALS. It is shown to improve motor skills and decrease TDP-43 proteotoxicity in a C. elegans model of ALS [143].

4.5. Epilepsy

Epilepsy is a serious neurological disorder that is known to affect about 70 million people globally. It exhibits a bunch of symptoms rather than a single complaint. It is categorized by a long-term predisposition that results in spontaneous epileptic seizures and leads to several neurobiological, psychosocial, and cognitive consequences. Epileptic seizures are persistent convulsive events characterized by conventional behavioral variations that show the basic neural mechanisms related to the disease [225,226]. Oxidative stress, inflammatory factors, and the unnecessary production and release of excitatory amino acids are known to play a key role in the pathology of epilepsy [227]. Many antiepileptic drugs are available nowadays, but these are ineffective in controlling epileptic seizures in about 30% of individuals suffering from epilepsy. Therefore, numerous approaches have been developed to produce novel medications for the treatment of epilepsy and a great emphasis is put on the use of natural products against epilepsy to reduce the side effects of chemical drugs [228,229].
The abundance of antioxidants present in honey has proven to exhibit beneficial roles against epilepsy. Quercetin is shown to have an ameliorating effect on epilepsy. It is shown to exert anti-inflammatory activity in kainic acid (KA)-induced models of epilepsy. It inhibits the activation of microglial cells and the subsequent release of inflammatory cytokines such as NF-κB, TNF-α, and IL-1β. It has also been reported to attenuate the seizures induced by KA. All these factors endorse an overall protective effect of honey against epilepsy [144]. Quercetin is reported to inhibit the expression of a gene for β subunits of GABA receptors which attenuates the progression of neurodegeneration in the KA-induced model of the seizure [145]. Quercetin supplementation, along with levetiracetam, reduces the depression associated with epilepsy. Depression in epilepsy is mainly caused by the predisposition of tryptophan levels. Quercetin restores tryptophan levels, thus diminishing the epilepsy comorbid depression [146]. Quercetin exerts a strong anticonvulsant effect in the maximal electric shock (MES) induced model of seizures in a dose-dependent manner. It does so by modulating the activities of glycinergic and GABAergic ion channels [147]. Quercetin-loaded nanoparticles exhibit anticonvulsant activity via reducing the behavioral signs of seizures, loss of neurons, and astrocyte activation in a pentylenetetrazol (PTZ)-induced kindling model [148].
Myricetin ameliorates the intensity of seizures and protects neuronal loss in the pentylenetetrazol-kindled mice model of epilepsy. It reduces the degeneration of neurons and inhibits apoptosis via the downregulation of Bad, Bax, and cleaved caspase-3 expression levels, along with the upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Myricetin normalizes the glutamate/GABA ratio which gets disturbed during epilepsy [149,150]. Luteolin has also been reported to be effective against epilepsy. Luteolin pre-treatment revokes the seizure elated cognitive deficits and reduces the severity of seizures in pentylenetetrazol-kindled mice. It causes an enhanced expression of Brain-Derived Neurotrophic Factor (BDNF), a factor essential for neuronal survival. It has also been reported to help in the mitigation of oxidative stress. Both these factors contribute to the improvement of cognitive functions [151]. Tambe et al. demonstrated that luteolin exerts an anticonvulsant effect by increasing the activation of receptors for GABAA, which facilitates the opening of chloride ion channels, and by enhancing the seizure threshold. Luteolin not only inhibits the production of seizures, but also diminishes oxidative stress via its free radical scavenging activity. These aspects support the anti-epileptogenic activity of luteolin and make it a potential candidate for epilepsy [152]. Luteolin could efficiently improve the cognition impairments in epileptic rats, and the underlying mechanism might be related to modulating the CaM-CaMPK signaling pathway via the downregulation of CaM, CaMPK, as well as the Ras protein [153].
Chrysin, another flavonoid present in honey, also exerts a neuroprotective effect against epilepsy. Chrysin attenuates the seizures induced by pentylenetetrazol in experimental models. It exhibits the anticonvulsant activity via the modulation of GABAA receptors and abrogates the convulsion-induced oxidative damage [154]. Chrysin-loaded nanoparticles lessen the severity of epileptic seizures and ameliorate the oxidative damage in the brains of pentylenetetrazol-kindled rats. Further, these particles reduce the process of apoptosis by boosting the expression of Nrf2, NQO-1, and HO-1. It supports that chrysin can act as a possible therapeutic approach to improve neurodegeneration in epilepsy [155]. Apigenin, another flavonoid, has also been suggested to be an effective neuroprotective agent against epilepsy. Apigenin employs a protective effect on kainite-induced memory impairments via an anticonvulsant and anti-apoptotic function. It reduces the neuronal loss in the hippocampus and the release of cytochrome c from the mitochondria which leads to the alleviation of apoptosis in the mitochondria [156]. Apigenin abrogates the myeloperoxidase-induced oxidative damage in the kainic acid-induced model of epilepsy. It inhibits the overexpression of hypochlorite (HClO). The production of hypochlorite (HClO) by myeloperoxidase is contemplated to be closely related to the development of epilepsy [157,158]. Sharma et al. revealed that apigenin averts the cognitive impairments, hence repairing the behavioral deficiencies, and exerts antidepressant and anti-anxiolytic effects in pentylenetetrazol-induced kindling models of epilepsy. These effects can be ascribed to an increased expression of BDNF via enhanced CREB and serotonin levels in the hippocampal region. Both serotonin and CREB are involved in the expression of the BDNF gene [159,230,231].
Ferulic acid, a phenolic acid, is another important component of honey that is effective against epilepsy. Supplementation of ferulic acid along with levetiracetam, an epileptic drug, palliates the epilepsy-associated depression in pentylenetetrazol-kindled animal models of epilepsy. Increased levels of proinflammatory cytokines and enhanced cyclooxygenase 2 (COX2) activity led to the upregulation of indoleamine 2,3-dioxygenase (IDO) activity and, consequently, causes depression in epileptic individuals [232,233]. Ferulic acid exerts an antidepressant effect via decreasing the levels of proinflammatory cytokines such as TNF-α and IL-1β, the inhibition of cyclooxygenase 2 (COX2) activity, the modulation of the corticosterone level, and repairing hypothalamus pituitary adrenal (HPA) axis dysfunction [160]. In another study, ferulic acid showed neuroprotective effects in models of epilepsy using pentylenetetrazol through the amelioration of oxidative stress and the upregulation of neuroprotective heat shock protein 70 (Hsp70), along with neurotransmitters such as serotonin (5-HT) and norepinephrine (NE) [161]. Hassanzadeh et al. reported that ferulic acid exerts an anti-epileptogenic effect via diminishing the oxidative stress, repairing the cognitive deficits, and decreasing the seizure activity [162]. Ferulic acid has also been shown to improve memory functions and learning capacities as well. Pre-treatment of animals with ferulic acid prevents the entylenetetrazol-induced oxidative, as well as cognitive, damage. It inhibits the apoptotic process via the activation of anti-apoptotic protein Bcl-2 and scavenges the free radicles to ameliorate oxidative damage [163].
Naringenin, another flavonoid, is a potential therapeutic agent against epilepsy. Naringenin exhibits a neuroprotective role against pilocarpine-induced epilepsy models. Pilocarpine causes the generation of seizures via the production of free radicals, which affects the respiratory chain inside the mitochondria, weakens the lysosomal membranes, and decreases the threshold for convulsions. Naringenin works as a strong antioxidant against pilocarpine-induced seizures. It causes an elevation in the levels of antioxidant enzymes, restores neuronal morphology, and reduces the neurodegeneration in the hippocampal area [164,234]. Granule cell disruption (GCD) occurring in the dentate gyrus (DG), an area of the hippocampus, is a pathological feature of temporal lobe epilepsy [235]. Naringenin is shown to impede the occurrence of seizures and decrease the kainic acid-instigated GCD in the hippocampus. Further, it ameliorates the generation of proinflammatory cytokines such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), which plays an antiepileptic role [165]. Naringenin shows an anticonvulsant effect in pentylenetetrazol- and MES-induced epilepsy models. This anticonvulsant role of naringenin is attributed to its antioxidant effect, agonist effect on GABAA receptors, and reduction of glutamate transmission [166].

4.6. Schizophrenia

Schizophrenia is a chronic, devastating neurodegenerative disorder known to affect more than 1% of the population across the globe. It causes the impairment of mental and social functions and often results in various comorbid diseases. Both men and women are affected in equal numbers. It is labeled by negative and positive symptoms. Hallucinations and delusions are the main positive symptoms of this disease, whereas negative symptoms include social withdrawal or isolation, lack of emotional expressiveness, and depression [168,236]. Instabilities of main cognitive processes such as executive functions, attention, and certain forms of memory (particularly working memory) are common among patients of schizophrenia, that combinedly lead to the behavioral alterations and functional disturbances of schizophrenia. Both genetic and environmental factors are involved in the development of this disorder [237].
Oxidative stress is an important underlying mechanism in the progression of the disease because the central nervous system is more susceptible to oxidative stress in comparison to other body organs. To combat oxidative damage, the use of antioxidants is a common and useful therapy against schizophrenia [238,239]. A study by Yahaya et al. showed that supplementing tualang honey to schizophrenic individuals for 8 weeks greatly affected their working memory. Tualang honey acts as a cognitive enhancer and improves learning abilities and cholinergic abnormalities in schizophrenia [240]. Antioxidants present in honey are also known to play vital roles against schizophrenia. Quercetin improved the cognitive impairments in a ketamine-induced mice model of schizophrenia. It exerts its effect via scavenging free radicals and increasing the levels of antioxidant enzymes [167]. Quercetin has also been reported to reduce the depressive behaviors in ketamine-instigated models of schizophrenia [168]. It also improves the behavioral impairments in schizophrenic models [169]. A case study report by Schwartz suggests that quercetin can be effectively used to boost antipsychotic therapy [170].

4.7. Depression

Depression is a serious mental illness that is known to affect more than 465 million people worldwide. According to the World Health Organization, depression is the second leading cause of disabilities across the globe. According to the American Psychological Association, depression is characterized by a lack of interest in nearly all activities, alterations in appetite, disturbed sleep, disordered psychomotor functions, feeling of uselessness and guilt, decreased decision-making abilities, thoughts of suicidal plans, and even suicidal attempts [241]. It is a complex pathophysiological condition that involves a diminution of the monoamine system, specifically in the neurotransmission of neurotransmitters including dopamine, serotonin (5HT), and norepinephrine, or the diminished functions of receptors for these neurotransmitters [242]. Impairments in functions of these neurotransmitters, mainly serotonin (5HT) and norepinephrine, lead to the development of depression [243,244,245]. Dysfunction of the immune system, both innate and adaptive, also occurs in depression. Elevation in the levels of inflammatory proteins and lower levels of BDNF are observed in patients with a mood disorder [246,247,248]. Oxidative stress is also considered a key player in the pathogenesis of the depressive disorder. Therefore, the use of antioxidants is considered an effective strategy against depression [249,250,251,252,253].
Honey is shown to be an effective prescription against depression owing to its antioxidant properties [254]. Polyphenols present in honey are considered an effective therapy in the cure and management of depressive disorders. Quercetin has been studied to exert antidepressant effects in the unpredictable chronic mild stress (UCMS) model of depression. It causes an increase in the levels of antioxidant enzymes, a decrease in the levels of inflammatory factors, and accrues serotonin (5HT) levels [171,172]. In a model of LPS-induced depression, quercetin mitigates depressive behavior by modulating levels of BDNF and its related factors [173]. Myricetin is also found useful in combating mood disorders. It recovers hopeless behavior in mice exposed to restraint stress for 21 days [174]. These protective effects are mainly due to the regulation of BDNF levels in the hippocampus and its antioxidant ability [175]. Kaempferol is reported to exert anti-depressive effects in a chronic social defeat stress (CSDS) mouse model. It causes an increase in the levels of antioxidant enzymes, decreases the levels of inflammatory cytokines, and upregulates the AKT/β-catenin cascade to overcome depression-like behaviors [176].
Chrysin, another flavonoid, is of major importance against depression. In mice subjected to chronic unpredictable mild stress (CUMS), chrysin is shown to exert protective effects through the upregulation of the nerve growth factor (NGF) and BDNF. It also normalizes Na+, K+-ATPase activity, which is compromised during the depression [177]. It employs anti-depressant effects in a model of agitated depression via the inhibition of the kynurenine pathway, the downregulation of inflammatory cytokines, and elevation in the levels of serotonin (5HT) and BDNF [178]. Naringenin exhibits potent anti-depressant effects. Bansal et al. reported that naringenin is quite beneficial against depression-like behaviors in the olfactory bulbectomized mice model of depression. It performs anti-depressive activity via the restoration of antioxidant enzymes’ levels, the elevation of BDNF levels, the modulation of serotonin levels, and the downregulation of inflammation mediators [179]. It alleviates depression-like behavioral instabilities caused by social defeat stress in mice through the inhibition of acetylcholinesterase activity, oxidative damage, and the release of inflammatory proteins [180]. It also causes the upregulation of BDNF, NKX2, PAX6, and sonic hedgehog (Shh) signaling to overcome the depression induced by CUMS [181].
Coumaric acid, a phenolic acid, has also been suggested as a potential therapeutic agent against depression. It improves behavioral hopelessness, lessens inflammation-associated alterations, enhances neurotrophic activity, and mitigates long-term synaptic depression (LTD) in the hippocampus induced by LPS [182]. Ferulic acid, another phenolic acid, also exhibits anti-depressive properties. In offspring rats subjected to prenatal stress (PS), ferulic acid treatment works as an anti-depressant. PS causes the upregulation of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and the expression of NF-κB and iNOS in the hippocampus which leads to the development of depression. Ferulic acid reverses all these changes and abrogates depression-like behaviors [183]. It has also been reported to ameliorate the depressive behaviors induced by LPS by downregulating the factors associated with inflammation and apoptosis [184].

5. Conclusions

Honey is a miraculous natural product with wonderful nutritional and therapeutic potential. It has been an important part of ethnomedicine since ancient times in every human civilization and culture for the cure and treatment of several maladies. In modern history, liquid gold has become an appreciable component of contemporary medicine used along with standard medical treatment for various ailments. Polyphenols present in honey have been proven to play vital roles against different neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Depression, etc. Nevertheless, further studies are needed to investigate the effects of honey, either individually or in combination with other complementary and alternative medicines, against various prevalent neurological disorders.

6. Limitations and Future Perspectives

Recent approaches toward the discovery of novel therapies for neurodegenerative disorders can be classified into four categories, namely protection against oxidative damage, reduction in neuroinflammation, the inhibition of enzymes that degrade neurotransmitters, and protection against neurotoxic environmental factors. All the studies included in the data cover the abovementioned approaches and provide comprehensive evidence in terms of the neuroprotective potential of polyphenols, but these are not enough to make a judgment about their clinical benefits. Moreover, there is a dearth of studies related to the direct use of honey against neurodegenerative diseases. Only a few studies on the direct use of honey against Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and schizophrenia were identified. Another limitation is the lack of any human study which backs up the cautionary measures in interpreting the effect of honey. Further studies are required to address these challenges and provide detailed mechanistic insight into the use of this liquid gold against neurodegeneration.

Author Contributions

Conceptualization, A.I., R.N. and H.A.; methodology, R.N. and H.M.; software, M.A.N. and M.F.; validation, M.K., A.A., F.A. and K.S.A.; formal analysis, A.I.; investigation, A.I.; resources, R.N.; data curation, H.A.; writing—original draft preparation, A.I., H.M., M.A.N., M.F. and M.K.; writing—review and editing, A.A., F.A. and K.S.A.; visualization, H.A.; supervision, H.A.; project administration, A.A.; funding acquisition, K.S.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The researchers would like to thank the Deanship of Scientific Research, Qassim University for funding the publication of this project.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Grossman, R. The Other Medicines: The Penicillin of Bees; Pan Books: London, UK, 1986; p. 177. [Google Scholar]
  2. Wootton, M.; Edwards, R.A.; Faraji-Haremi, R.; Williams, P.J. Effect of accelerated storage conditions on the chemical composition and properties of Australian honeys. J. Apic. Res. 1978, 17, 167–172. [Google Scholar] [CrossRef]
  3. Majno, G. The Healing Hand: Man and Wound in the Ancient World; Harvard University Press: Cambridge, MA, USA, 1991. [Google Scholar]
  4. Asadi-Pooya, A.A.; Pnjehshahin, M.R.; Beheshti, S. The antimycobacterial effect of honey: An in vitro study. Riv. Biol. 2003, 96, 491–495. [Google Scholar] [PubMed]
  5. Hippocrates. On the articulations. The genuine works of Hippocrates. Clin. Orthop. Relat. Res. 2002, 400, 19–25. [Google Scholar]
  6. Molan, P.C. Why honey is effective as a medicine. Its use in modern medicine. Bee World 1999, 80, 80–92. [Google Scholar] [CrossRef]
  7. White, J.W., Jr.; Hoban, N. Composition of honey. IV. Identification of the disaccharides. Arch. Biochem. Biophys. 1959, 80, 386–392. [Google Scholar] [CrossRef]
  8. White, J.W., Jr. The composition of honey. Bee World 1957, 80, 386–392. [Google Scholar] [CrossRef]
  9. Eteraf-Oskouei, T.; Najafi, M. Traditional and modern uses of natural honey in human diseases: A review. Iran. J. Basic. Med. Sci. 2013, 16, 731–742. [Google Scholar]
  10. Michiu, D.; Socaciu, M.I.; Fogarasi, M.; Jimborean, A.M.; Ranga, F.; Mureşan, V.; Semeniuc, C.A. Implementation of an Analytical Method for Spectrophotometric Evaluation of Total Phenolic Content in Essential Oils. Molecules 2022, 27, 1345. [Google Scholar] [CrossRef]
  11. Biesaga, M.; Pyrzyńska, K. Stability of bioactive polyphenols from honey during different extraction methods. Food Chem. 2013, 136, 46–54. [Google Scholar] [CrossRef]
  12. Pyrzynska, K.; Biesaga, M. Analysis of phenolic acids and flavonoids in honey. TrAC-Trend Anal. Chem. 2009, 28, 893–902. [Google Scholar] [CrossRef]
  13. Khalil, M.I.; Sulaiman, S.A. The potential role of honey and its polyphenols in preventing heart diseases: A review. Afr. J. Tradit. Complement. Altern. Med. 2010, 7, 315–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Hossen, M.S.; Ali, M.Y.; Jahurul, M.H.; Abdel-Daim, M.M.; Gan, S.H.; Khalil, M.I. Beneficial roles of honey polyphenols against some human degenerative diseases: A review. Pharmacol. Rep. 2017, 69, 1194–1205. [Google Scholar] [CrossRef] [PubMed]
  15. Yao, L.; Datta, N.; Tomas-Barberan, F.A.; Ferreres, F.; Martos, I.; Singanusong, R. Flavonoids, phenolic acids and abscisic acid in Australian and New Zealand Leptospermum honeys. Food Chem. 2003, 81, 159–168. [Google Scholar] [CrossRef]
  16. Deng, J.; Liu, R.; Lu, Q.; Hao, P.; Xu, A.; Zhang, J.; Tan, J. Biochemical properties, antibacterial and cellular antioxidant activities of buckwheat honey in comparison to manuka honey. Food Chem. 2018, 252, 243–249. [Google Scholar] [CrossRef]
  17. Stephens, J.M.; Schlothauer, R.C.; Morris, B.D.; Yang, D.; Fearnley, L.; Greenwood, D.R.; Loomes, K.M. Phenolic compounds and methylglyoxal in some New Zealand manuka and kanuka honeys. Food Chem. 2010, 120, 78–86. [Google Scholar] [CrossRef]
  18. Šarić, G.; Vahčić, N.; Bursać Kovačević, D.; Putnik, P. The changes of flavonoids in honey during storage. Processes 2020, 8, 943. [Google Scholar] [CrossRef]
  19. Marghitas, L.A.; Dezmirean, D.S.; Pocol, C.B.; Marioara, I.L.; Bobis, O.; Gergen, I. The development of a biochemical profile of acacia honey by identifying biochemical determinants of its quality. Not. Bot. Horti. Agrobot. Cluj-Napoca 2010, 38, 84–90. [Google Scholar]
  20. Martos, I.; Ferreres, F.; Yao, L.; D’Arcy, B.; Caffin, N.; Tomás-Barberán, F.A. Flavonoids in monospecific eucalyptus honeys from Australia. J. Agric. Food. Chem. 2000, 48, 4744–4748. [Google Scholar] [CrossRef]
  21. Perna, A.; Intaglietta, I.; Simonetti, A.; Gambacorta, E. A comparative study on phenolic profile, vitamin C content and antioxidant activity of Italian honeys of different botanical origin. Int. J. Food Sci. Technol. 2013, 48, 1899–1908. [Google Scholar] [CrossRef]
  22. Kıvrak, Ş.; Kıvrak, İ. Assessment of phenolic profile of Turkish honeys. Int. J. Food Prop. 2017, 20, 864–876. [Google Scholar] [CrossRef] [Green Version]
  23. Kečkeš, S.; Gašić, U.; Veličković, T.Ć.; Milojković-Opsenica, D.; Natić, M.; Tešić, Ž. The determination of phenolic profiles of Serbian unifloral honeys using ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry. Food Chem. 2013, 138, 32–40. [Google Scholar] [CrossRef] [PubMed]
  24. Hamdy, A.A.; Ismail, H.M.; Al-Ahwal, A.-M.; Gomaa, N.F. Determination of flavonoid and phenolic Acid contents of clover, cotton and citrus floral honeys. J. Egypt. Public Health Assoc. 2009, 84, 245–259. [Google Scholar] [PubMed]
  25. Zumla, A.; Lulat, A. Honey—A remedy rediscovered. J. R. Soc. Med. 1989, 82, 384–385. [Google Scholar] [CrossRef] [Green Version]
  26. Mohamed, M.; Sirajudeen, K.N.; Swamy, M.; Yaacob, M.; Sulaiman, S. Studies on the antioxidant properties of Tualang honey of Malaysia. Afr. J. Tradit. Complement. Altern. Med. 2010, 7, 59–63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Abeshu, M.A.; Geleta, B. Medicinal uses of honey. Biol. Med. 2016, 8, 1. [Google Scholar]
  28. Swellam, T.; Miyanaga, N.; Onozawa, M.; Hattori, K.; Kawai, K.; Shimazui, T.; Akaza, H. Antineoplastic activity of honey in an experimental bladder cancer implantation model: In vivo and in vitro studies. Int. J. Urol. 2003, 10, 213–219. [Google Scholar] [CrossRef] [Green Version]
  29. Kumar, K.S.; Bhowmik, D.; Biswajit, C.; Chandira, M.R. Medicinal uses and health benefits of honey: An overview. J. Chem. Pharm. Res. 2010, 2, 385–395. [Google Scholar]
  30. Dustmann, J.H. Antibacterial effect of honey. Apiacta 1979, 14, 7–11. [Google Scholar]
  31. Johnston, M.; McBride, M.; Dahiya, D.; Owusu-Apenten, R.; Nigam, P.S. Antibacterial activity of Manuka honey and its components: An overview. AIMS Microbiol. 2018, 4, 655–664. [Google Scholar] [CrossRef]
  32. Albaridi, N.A. Antibacterial Potency of Honey. Int. J. Microbiol. 2019, 2019, 2464507. [Google Scholar] [CrossRef]
  33. Onifade, A.A.; Jewell, A.P.; Ajadi, T.A.; Rahamon, S.K.; Ogunrin, O.O. Effectiveness of a herbal remedy in six HIV patients in Nigeria. J. Herb. Med. 2013, 3, 99–103. [Google Scholar] [CrossRef]
  34. Fingleton, J.; Corin, A.; Sheahan, D.; Cave, N.; Braithwaite, I.; Weatherall, M.; Beasley, R. Randomised controlled trial of topical kanuka honey for the treatment of cold sores. Adv. Integr. Med. 2014, 1, 119–123. [Google Scholar] [CrossRef]
  35. Anyanwu, C.U. Investigation of in vitro antifungal activity of honey. J. Med. Plants Res. 2012, 6, 3512–3516. [Google Scholar] [CrossRef]
  36. Ahmad, K.; Khali, A.T.; Somayya, R.; Khan, F.N.; Shah, A.R.; Ovais, M.; Shinwari, Z.K. Potential antifungal activity of different honey brands from Pakistan: A quest for natural remedy. Afr. J. Tradit. Complement. Altern. Med. 2017, 14, 18–23. [Google Scholar] [CrossRef] [Green Version]
  37. Hau-Yama, N.E.; Magaña-Ortiz, D.; Oliva, A.I.; Ortiz-Vázquez, E. Antifungal activity of honey from stingless bee Melipona beecheii against Candida albicans. J. Apic. Res. 2020, 59, 12–18. [Google Scholar] [CrossRef]
  38. Erejuwa, O.O.; Sulaiman, S.A.; Ab Wahab, M.S. Honey: A novel antioxidant. Molecules 2012, 17, 4400–4423. [Google Scholar] [CrossRef]
  39. Gül, A.; Pehlivan, T. Antioxidant activities of some monofloral honey types produced across Turkey. Saudi. J. Biol. Sci. 2018, 25, 1056–1065. [Google Scholar] [CrossRef]
  40. Dżugan, M.; Tomczyk, M.; Sowa, P.; Grabek-Lejko, D. Antioxidant Activity as Biomarker of Honey Variety. Molecules 2018, 23, 2069. [Google Scholar] [CrossRef] [Green Version]
  41. Almasaudi, S.B.; Abbas, A.T.; Al-Hindi, R.R.; El-Shitany, N.A.; Abdel-Dayem, U.A.; Ali, S.S.; Saleh, R.M.; Al Jaouni, S.K.; Kamal, M.A.; Harakeh, S.M. Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats. Evid. Based. Complement. Altern. Med. 2017, 2017, 5413917. [Google Scholar] [CrossRef]
  42. Ghazali, W.S.; Romli, A.C.; Mohamed, M. Effects of honey supplementation on inflammatory markers among chronic smokers: A randomized controlled trial. BMC Complement. Altern. Med. 2017, 17, 175. [Google Scholar] [CrossRef]
  43. Minden-Birkenmaier, B.A.; Cherukuri, K.; Smith, R.A.; Radic, M.Z.; Bowlin, G.L. Manuka honey modulates the inflammatory behavior of a dHL-60 neutrophil Model under the cytotoxic limit. Int. J. Biomater. 2019, 2019, 6132581. [Google Scholar] [CrossRef] [PubMed]
  44. Hassan, M.I.; Mabrouk, G.M.; Shehata, H.H.; Aboelhussein, M.M. Antineoplastic effects of bee honey and Nigella sativa on hepatocellular carcinoma cells. Integr. Cancer. Ther. 2012, 11, 354–363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Efem, S.E.; Udoh, K.T.; Iwara, C.I. The antimicrobial spectrum of honey and its clinical significance. Infection 1992, 20, 227–229. [Google Scholar] [CrossRef] [PubMed]
  46. Almasaudi, S.B.; Al-Nahari, A.A.M.; Abd El-Ghany, E.S.M.; Barbour, E.; Al Muhayawi, S.M.; Al-Jaouni, S.; Azhar, E.; Qari, M.; Qari, Y.A.; Harakeh, S. Antimicrobial effect of different types of honey on Staphylococcus aureus. Saudi J. Biol. Sci. 2017, 24, 1255–1261. [Google Scholar] [CrossRef] [Green Version]
  47. Bouzo, D.; Cokcetin, N.N.; Li, L.; Ballerin, G.; Bottomley, A.L.; Lazenby, J.; Whitchurch, C.B.; Paulsen, I.T.; Hassan, K.A.; Harry, E.J. Characterizing the mechanism of action of an ancient antimicrobial, Manuka honey, against Pseudomonas aeruginosa using modern transcriptomics. MSystems 2020, 5, e00106-20. [Google Scholar] [CrossRef]
  48. Ahmed, S.; Othman, N.H. The anti-cancer effects of Tualang honey in modulating breast carcinogenesis: An experimental animal study. BMC Complement. Altern. Med. 2017, 17, 208. [Google Scholar] [CrossRef] [Green Version]
  49. Aryappalli, P.; Al-Qubaisi, S.S.; Attoub, S.; George, J.A.; Arafat, K.; Ramadi, K.B.; Mohamed, Y.A.; Al-Dhaheri, M.M.; Al-Sbiei, A.; Fernandez-Cabezudo, M.J.; et al. The IL-6/STAT3 signaling pathway is an early target of manuka honey-induced suppression of human breast cancer cells. Front. Oncol. 2017, 7, 167. [Google Scholar] [CrossRef] [Green Version]
  50. Taban, Q.; Mumtaz, P.T.; Ali, A. Honey in Anticancer Drug Toxicity. In Therapeutic Applications of Honey and Its Phytochemicals; Springer: Berlin, Germany, 2020; pp. 307–324. [Google Scholar]
  51. Najafi, M.; Mahdizadeh, A.E.; Rafiei, F.; Eteraf, O.T. Effects of pharmacologic preconditioning by natural honey on arrhythmias and infarct size in isolated heart. Pharm. Sci. 2008, 4, 1–11. [Google Scholar]
  52. Najafi, M.; Shaseb, E.; Ghaffary, S.; Fakhrju, A.; Eteraf Oskouei, T. Effects of chronic oral administration of natural honey on ischemia/reperfusion-induced arrhythmias in isolated rat heart. Iran. J. Basic Med. Sci. 2011, 14, 75–81. [Google Scholar]
  53. Zeina, B.; Zohra, B.I.; Al-Assad, S. The effects of honey on Leishmania parasites: An in vitro study. Trop. Doct. 1997, 27 (Suppl. S1), 36–38. [Google Scholar]
  54. Gharirvand Eskandari, E.; Setorki, M.; Doudi, M. Medicinal plants with antileishmanial properties: A review study. Pharm. Biomed. Res. 2020, 6, 1–16. [Google Scholar] [CrossRef]
  55. Ahmed, A.; Khan, R.A.; Azim, M.K.; Saeed, S.A.; Mesaik, M.A.; Ahmed, S.; Imran, I. Effect of natural honey on human platelets and blood coagulation proteins. Pak. J. Pharm. Sci. 2011, 24, 389–397. [Google Scholar] [PubMed]
  56. Olas, B. Honey and its phenolic compounds as an effective natural medicine for cardiovascular diseases in humans? Nutrients 2020, 12, 283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Wang, X.H.; Andrae, L.; Engeseth, N.J. Antimutagenic effect of various honeys and sugars against Trp-p-1. J. Agric. Food. Chem. 2002, 50, 6923–6928. [Google Scholar] [CrossRef] [PubMed]
  58. Saxena, S.; Gautam, S.; Maru, G.; Kawle, D.; Sharma, A. Suppression of error prone pathway is responsible for antimutagenic activity of honey. Food. Chem. Toxicol. 2012, 50, 625–633. [Google Scholar] [CrossRef]
  59. Azim, M.K.; Perveen, H.; Mesaik, M.A.; Simjee, S.U. Antinociceptive activity of natural honey in thermal-nociception models in mice. Phytother. Res. 2007, 21, 194–197. [Google Scholar] [CrossRef]
  60. Geißler, K.; Schulze, M.; Inhestern, J.; Meißner, W.; Guntinas-Lichius, O. The effect of adjuvant oral application of honey in the management of postoperative pain after tonsillectomy in adults: A pilot study. PLoS ONE 2020, 15, e0228481. [Google Scholar] [CrossRef]
  61. Hannan, A.; Munir, S.; Arshad, M.U.; Bashir, N. In Vitro Antimycobacterial Activity of Pakistani Beri Honey Using BACTEC MGIT 960. Int. Sch. Res. Not. 2014, 2014, 490589. [Google Scholar] [CrossRef] [Green Version]
  62. Ghashm, A.A.; Othman, N.H.; Khattak, M.N.; Ismail, N.M.; Saini, R. Antiproliferative effect of Tualang honey on oral squamous cell carcinoma and osteosarcoma cell lines. BMC Complement. Altern. Med. 2010, 10, 49. [Google Scholar] [CrossRef] [Green Version]
  63. Mumtaz, P.T.; Bashir, S.M.; Rather, M.A.; Dar, K.B.; Taban, Q.; Sajood, S.; Ali, A.; Rather, Z.A.; Amin, I.; Dar, M.A. Antiproliferative and Apoptotic Activities of Natural Honey. In Therapeutic Applications of Honey and Its Phytochemicals; Springer: Singapore, 2020; pp. 345–360. [Google Scholar]
  64. Kassim, M.; Mansor, M.; Achoui, M.; Yan, O.S.; Devi, S.; Yusoff, K.M. Honey as an immunomodulator during sepsis in animal model. Critical Care 2009, 13, 1–2. [Google Scholar] [CrossRef] [Green Version]
  65. Babaei, S.; Rahimi, S.; Torshizi, M.A.; Tahmasebi, G.; Miran, S.N. Effects of propolis, royal jelly, honey and bee pollen on growth performance and immune system of Japanese quails. Vet. Res. Forum. 2016, 7, 13–20. [Google Scholar] [PubMed]
  66. Wusiman, A.; Xu, S.; Ni, H.; Gu, P.; Liu, Z.; Zhang, Y.; Qiu, T.; Hu, Y.; Liu, J.; Wu, Y.; et al. Immunomodulatory effects of Alhagi honey polysaccharides encapsulated into PLGA nanoparticles. Carbohydr. Polym. 2019, 211, 217–226. [Google Scholar] [CrossRef] [PubMed]
  67. Ariantari, N.P.; Yowani, S.C.; Swastini, D.A. UJji aktivitas penurunan kolesterol produk madu herbal yang beredar di pasaran pada tikus putih diet lemak tinggi [hypocholesterolemic activity of marketed herbal honey products in albino rats with hypercholesterolemic diet]. J. Kimia 2010, 4, 15–19. [Google Scholar]
  68. Mohamed, Z.B.; Alfarisi, H.A.; Wahab, A.Y.; binti Abd Fuaat, A.; Mohamad, C.A.; Ibrahim, M. Hypocholesterolemic and anti-inflammatory effects of trihoney in hypercholesterolemic rabbit model. Int. J. Allied Health Sci. 2019, 3, 846. [Google Scholar]
  69. Khalil, M.I.; Tanvir, E.M.; Afroz, R.; Sulaiman, S.A.; Gan, S.H. Cardioprotective Effects of Tualang Honey: Amelioration of Cholesterol and Cardiac Enzymes Levels. Biomed. Res. Int. 2015, 2015, 286051. [Google Scholar] [CrossRef] [Green Version]
  70. Bt Hj Idrus, R.; Sainik, N.Q.; Nordin, A.; Saim, A.B.; Sulaiman, N. Cardioprotective Effects of Honey and Its Constituent: An Evidence-Based Review of Laboratory Studies and Clinical Trials. Int. J. Environ. Res. Public Health 2020, 17, 3613. [Google Scholar] [CrossRef]
  71. Erejuwa, O.O.; Sulaiman, S.A.; Ab Wahab, M.S.; Sirajudeen, K.N.; Salleh, S.; Gurtu, S. Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress. Oxid. Med. Cell. Longev. 2012, 2012, 374037. [Google Scholar] [CrossRef] [Green Version]
  72. Erejuwa, O.O.; Sulaiman, S.A.; Wahab, M.S.; Sirajudeen, K.N.; Salleh, M.S.; Gurtu, S. Hepatoprotective effect of tualang honey supplementation in streptozotocin-induced diabetic rats. Int. J. Appl. Res. Nat. Prod. 2012, 4, 37–41. [Google Scholar]
  73. Zhao, H.; Cheng, N.; He, L.; Peng, G.; Liu, Q.; Ma, T.; Cao, W. Hepatoprotective effects of the honey of apis cerana fabricius on bromobenzene-induced liver damage in mice. J. Food. Sci. 2018, 83, 509–516. [Google Scholar] [CrossRef]
  74. Gharzouli, K.; Amira, S.; Gharzouli, A.; Hennouf, S. Gastroprotective effects of honey and glucose-fructose-sucrose-maltose mixture against ethanol-, indomethacin-, and acidified aspirin-induced lesions in the rat. Exp. Toxicol. Pathol. 2002, 54, 217–221. [Google Scholar] [CrossRef]
  75. Qaid, A.; Yaseen, E. Neuroprotective Effects of Tualang Honey in Male Rats Exposed to Normobaric Hypoxia. Ph.D. Thesis, Kampus Kesihatan, Universiti Sains Malaysia, Penang, Malaysia, 2017. [Google Scholar]
  76. Azman, K.F.; Zakaria, R.; Othman, Z.; Abdul Aziz, C.B. Neuroprotective effects of Tualang honey against oxidative stress and memory decline in young and aged rats exposed to noise stress. J. Taibah Univ. Sci. 2018, 12, 273–284. [Google Scholar] [CrossRef] [Green Version]
  77. Ibrahim, A.; Eldaim, M.A.; Abdel-Daim, M.M. Nephroprotective effect of bee honey and royal jelly against subchronic cisplatin toxicity in rats. Cytotechnology 2016, 68, 1039–1048. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Obia, O.; Odum, J.E.; Chuemere, A.N. Nephroprotective and antihyperlipidemic activity honey in alloxan-induced diabetic rats. Int. J. Biochem. Res. Rev. 2018, 22, 1–7. [Google Scholar] [CrossRef]
  79. Erejuwa, O.O.; Gurtu, S.; Sulaiman, S.A.; Ab Wahab, M.S.; Sirajudeen, K.N.; Salleh, M.S. Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats. Int. J. Vitam. Nutr. Res. 2010, 80, 74–82. [Google Scholar] [PubMed]
  80. El-Haskoury, R.; Al-Waili, N.; El-Hilaly, J.; Al-Waili, W.; Lyoussi, B. Antioxidant, hypoglycemic, and hepatoprotective effect of aqueous and ethyl acetate extract of carob honey in streptozotocin-induced diabetic rats. Vet. World 2019, 12, 1916. [Google Scholar] [CrossRef] [PubMed]
  81. Mohamed, M.; Sulaiman, S.A.; Jaafar, H.; Sirajudeen, K.N. Antioxidant protective effect of honey in cigarette smoke-induced testicular damage in rats. Int. J. Mol. Sci. 2011, 12, 5508–5521. [Google Scholar] [CrossRef] [Green Version]
  82. Sharifah, D. Effects of nicotine and Gelam honey on testis parameters and sperm qualities of juvenile rats. Sci. Res. Essays. 2011, 6, 5471–5474. [Google Scholar]
  83. Zaid, S.S.; Sulaiman, S.A.; Sirajudeen, K.N.; Othman, N.H. The effects of Tualang honey on female reproductive organs, tibia bone and hormonal profile in ovariectomised rats—Animal model for menopause. BMC Complement. Altern. Med. 2010, 10, 82. [Google Scholar] [CrossRef] [Green Version]
  84. Zaid, S.S.; Othman, S.; Kassim, N.M. Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat. BMC Complement. Altern. Med. 2014, 14, 509. [Google Scholar] [CrossRef] [Green Version]
  85. Carroll, W.M. The global burden of neurological disorders. Lancet Neurol. 2019, 18, 418–419. [Google Scholar] [CrossRef] [Green Version]
  86. Salim, S. Oxidative Stress and the Central Nervous System. J. Pharmacol. Exp. Ther. 2017, 360, 201–205. [Google Scholar] [CrossRef] [PubMed]
  87. Wieczorek, J.; Pietrzak, M.; Pomianowski, J.; Wieczorek, Z. Honey as a source of bioactive compounds. Pol. J. Nat. Sci. 2014, 29, 275–285. [Google Scholar]
  88. Mijanur Rahman, M.; Gan, S.H.; Khalil, M.I. Neurological effects of honey: Current and future prospects. Evid. Based Complement. Altern. Med. 2014, 2014, 958721. [Google Scholar] [CrossRef] [PubMed]
  89. Funakoshi, T.; Kanzaki, N.; Otsuka, Y.; Izumo, T.; Shibata, H.; Machida, S. Quercetin inhibits adipogenesis of muscle progenitor cells in vitro. Biochem. Biophys. Rep. 2017, 13, 39–44. [Google Scholar] [CrossRef] [PubMed]
  90. Li, Y.; Tian, Q.; Li, Z.; Dang, M.; Lin, Y.; Hou, X. Activation of Nrf2 signaling by sitagliptin and quercetin combination against β-amyloid induced Alzheimer’s disease in rats. Drug. Dev. Res. 2019, 80, 837–845. [Google Scholar] [CrossRef] [PubMed]
  91. Zaplatic, E.; Bule, M.; Shah, S.Z.A.; Uddin, M.S.; Niaz, K. Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci. 2019, 224, 109–119. [Google Scholar] [CrossRef]
  92. Sabogal-Guáqueta, A.M.; Munoz-Manco, J.I.; Ramírez-Pineda, J.R.; Lamprea-Rodriguez, M.; Osorio, E.; Cardona-Gómez, G.P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 2015, 93, 134–145. [Google Scholar] [CrossRef] [Green Version]
  93. Moreno, L.C.G.E.I.; Puerta, E.; Suárez-Santiago, J.E.; Santos-Magalhães, N.S.; Ramirez, M.J.; Irache, J.M. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int. J. Pharm. 2017, 517, 50–57. [Google Scholar] [CrossRef]
  94. Ramezani, M.; Darbandi, N.; Khodagholi, F.; Hashemi, A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer’s disease. Neural Regen. Res. 2016, 11, 1976. [Google Scholar] [CrossRef]
  95. Semwal, D.K.; Semwal, R.B.; Combrinck, S.; Viljoen, A. Myricetin: A Dietary Molecule with Diverse Biological Activities. Nutrients 2016, 8, 90. [Google Scholar] [CrossRef] [Green Version]
  96. Wang, B.; Zhong, Y.; Gao, C.; Li, J. Myricetin ameliorates scopolamine-induced memory impairment in mice via inhibiting acetylcholinesterase and down-regulating brain iron. Biochem. Biophys. Res. Commun. 2017, 490, 336–342. [Google Scholar] [CrossRef] [PubMed]
  97. Chen, H.; Lin, H.; Xie, S.; Huang, B.; Qian, Y.; Chen, K.; Niu, Y.; Shen, H.M.; Cai, J.; Li, P.; et al. Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination. Toxicol. Appl. Pharmacol. 2019, 365, 19–29. [Google Scholar] [CrossRef] [PubMed]
  98. Chanput, W.; Krueyos, N.; Ritthiruangdej, P. Anti-oxidative assays as markers for anti-inflammatory activity of flavonoids. Int. Immunopharmacol. 2016, 40, 170–175. [Google Scholar] [CrossRef]
  99. Park, K.S.; Chong, Y.; Kim, M.K. Myricetin: Biological activity related to human health. Appl. Biol. Chem. 2016, 59, 259–269. [Google Scholar] [CrossRef]
  100. Beg, T.; Jyoti, S.; Naz, F.; Rahul Ali, F.; Ali, S.K.; Reyad, A.M.; Siddique, Y.H. Protective Effect of Kaempferol on the Transgenic Drosophila Model of Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets. 2018, 17, 421–429. [Google Scholar] [CrossRef] [PubMed]
  101. Kouhestani, S.; Jafari, A.; Babaei, P. Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Regen. Res. 2018, 13, 1827. [Google Scholar]
  102. Kim, J.H.; Lee, S.; Cho, E.J.; Kim, H.Y. Neuroprotective effects of kaempferol, quercetin, and its glycosides by regulation of apoptosis. J. Korea Acad.-Ind. Corp. Soc. 2019, 20, 286–293. [Google Scholar]
  103. Darbandi, N.; Ramezani, M.; Khodagholi, F.; Noori, M. Kaempferol promotes memory retention and density of hippocampal CA1 neurons in intra-cerebroventricular STZ-induced experimental AD model in Wistar rats. Biologija 2016, 62. [Google Scholar] [CrossRef] [Green Version]
  104. Kim, J.H.; Kim, H.Y.; Cho, E.J. Protective effects of kaempferol, quercetin, and its glycosides on amyloid beta-induced neurotoxicity in C6 glial cell. J. Appl. Biol. Chem. 2019, 62, 327–332. [Google Scholar] [CrossRef] [Green Version]
  105. Pate, K.M.; Rogers, M.; Reed, J.W.; van der Munnik, N.; Vance, S.Z.; Moss, M.A. Anthoxanthin polyphenols attenuate aβ oligomer-induced neuronal responses associated with Alzheimer’s disease. CNS Neurosci. Ther. 2017, 23, 135–144. [Google Scholar] [CrossRef]
  106. Ali, F.; Siddique, Y.H. Bioavailability and Pharmaco-therapeutic Potential of Luteolin in Overcoming Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets 2019, 18, 352–365. [Google Scholar] [CrossRef] [PubMed]
  107. Wang, H.; Wang, H.; Cheng, H.; Che, Z. Ameliorating effect of luteolin on memory impairment in an Alzheimer’s disease model. Mol. Med. Rep. 2016, 13, 4215–4220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Huang, L.; Lin, M.; Zhong, X.; Yang, H.; Deng, M. Galangin decreases p-tau, Aβ42 and β-secretase levels, and suppresses autophagy in okadaic acid-induced PC12 cells via an Akt/GSK3β/mTOR signaling-dependent mechanism. Mol. Med. Rep. 2019, 19, 1767–1774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Kilic, F.S.; Kaygisiz, B.; Aydin, S.; Yildirim, E.; Oner, S.; Erol, K. The effects and mechanisms of the action of galangin on spatial memory in rats. Bratisl. Lek. Listy 2019, 120, 881–886. [Google Scholar] [CrossRef] [PubMed]
  110. Wang, Y.; Wang, Y.; Li, J.; Hua, L.; Han, B.; Zhang, Y.; Yang, X.; Zeng, Z.; Bai, H.; Yin, H.; et al. Effects of caffeic acid on learning deficits in a model of Alzheimer’s disease. Int. J. Mol. Med. 2016, 38, 869–875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Chandra, S.; Roy, A.; Jana, M.; Pahan, K. Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer’s disease mouse model. Neurobiol. Dis. 2019, 124, 379–395. [Google Scholar] [CrossRef]
  112. Ay, M.; Luo, J.; Langley, M.; Jin, H.; Anantharam, V.; Kanthasamy, A.; Kanthasamy, A.G. Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson’s Disease. J. Neurochem. 2017, 141, 766–782. [Google Scholar] [CrossRef]
  113. Ghaffari, F.; Moghaddam, A.H.; Zare, M. Neuroprotective effect of quercetin nanocrystal in a 6-hydroxydopamine model of parkinson disease: Biochemical and behavioral evidence. Basic Clin. Neurosci. 2018, 9, 317. [Google Scholar] [CrossRef]
  114. El-Horany, H.E.; El-latif, R.N.; ElBatsh, M.M.; Emam, M.N. Ameliorative effect of quercetin on neurochemical and behavioral deficits in rotenone rat model of Parkinson’s disease: Modulating autophagy (quercetin on experimental Parkinson’s disease). J. Biochem. Mol. Toxicol. 2016, 30, 360–369. [Google Scholar] [CrossRef]
  115. Ara, G.; Afzal, M.; Jyoti, S.; Naz, F.; Siddique, Y.H. Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease. Curr. Drug Ther. 2019, 14, 58–64. [Google Scholar] [CrossRef]
  116. Huang, B.; Liu, J.; Ma, D.; Chen, G.; Wang, W.; Fu, S. Myricetin prevents dopaminergic neurons from undergoing neuroinflammation-mediated degeneration in a lipopolysaccharide-induced Parkinson’s disease model. J. Funct. Foods 2018, 45, 452–461. [Google Scholar] [CrossRef]
  117. Guo, B.; Zheng, C.; Cai, W.; Cheng, J.; Wang, H.; Li, H.; Sun, Y.; Cui, W.; Wang, Y.; Han, Y.; et al. Multifunction of Chrysin in Parkinson’s Model: Anti-Neuronal Apoptosis, Neuroprotection via Activation of MEF2D, and Inhibition of Monoamine Oxidase-B. J. Agric. Food Chem. 2016, 64, 5324–5333. [Google Scholar] [CrossRef] [PubMed]
  118. Del Fabbro, L.; Rossito Goes, A.; Jesse, C.R.; de Gomes, M.G.; Cattelan Souza, L.; Lobo Ladd, F.V.; Lobo Ladd, A.A.B.; Nunes Arantes, R.V.; Reis Simionato, A.; Oliveira, M.S.; et al. Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson’s disease. Neurosci. Lett. 2019, 706, 158–163. [Google Scholar] [CrossRef] [PubMed]
  119. Ahmed, M.R.; Shaikh, M.A.; Ul Haq, S.H.I.; Nazir, S. Neuroprotective role of chrysin in attenuating loss of dopaminergic neurons and improving motor, learning and memory functions in rats. Int. J. Health Sci. 2018, 12, 35–43. [Google Scholar]
  120. Khatri, D.K.; Juvekar, A.R. Kinetics of Inhibition of Monoamine Oxidase Using Curcumin and Ellagic Acid. Pharmacogn. Mag. 2016, 12 (Suppl. S2), S116–S120. [Google Scholar]
  121. Sarkaki, A.; Farbood, Y.; Dolatshahi, M.; Mansouri, S.M.; Khodadadi, A. Neuroprotective Effects of Ellagic Acid in a Rat Model of Parkinson’s Disease. Acta Med. Iran. 2016, 54, 494–502. [Google Scholar]
  122. Baluchnejadmojarad, T.; Rabiee, N.; Zabihnejad, S.; Roghani, M. Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease: Possible involvement of ERβ/Nrf2/HO-1 signaling. Brain Res. 2017, 1662, 23–30. [Google Scholar] [CrossRef]
  123. Prorok, T.; Jana, M.; Patel, D.; Pahan, K. Cinnamic acid protects the nigrostriatum in a mouse model of Parkinson’s disease via peroxisome proliferator-activated receptorα. Neurochem. Res. 2019, 44, 751–762. [Google Scholar] [CrossRef]
  124. Chen, G.; Liu, J.; Jiang, L.; Ran, X.; He, D.; Li, Y.; Huang, B.; Wang, W.; Fu, S. Galangin Reduces the Loss of Dopaminergic Neurons in an LPS-Evoked Model of Parkinson’s Disease in Rats. Int. J. Mol Sci. 2017, 19, 12. [Google Scholar] [CrossRef] [Green Version]
  125. Choi, M.J.; Lee, E.J.; Park, J.S.; Kim, S.N.; Park, E.M.; Kim, H.S. Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: Critical role of PPAR-γ signaling pathway. Biochem. Pharmacol. 2017, 144, 120–131. [Google Scholar] [CrossRef]
  126. Chaturvedi, R.K.; Beal, M.F. PPAR: A therapeutic target in Parkinson’s disease. J. Neurochem. 2008, 106, 506–518. [Google Scholar] [CrossRef] [PubMed]
  127. Carta, A.R. PPAR-γ: Therapeutic prospects in Parkinson’s disease. Curr. Drug. Targets 2013, 14, 743–751. [Google Scholar] [CrossRef] [PubMed]
  128. Siddique, Y.H.; Jyoti, S. Alteration in biochemical parameters in the brain of transgenic Drosophila melanogaster model of Parkinson’s disease exposed to apigenin. Integr. Med. Res. 2017, 6, 245–253. [Google Scholar] [CrossRef]
  129. Sandhir, R.; Mehrotra, A. Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington’s disease. Biochim. Biophys. Acta. Mol. Basis Dis. 2013, 1832, 421–430. [Google Scholar] [CrossRef] [Green Version]
  130. Chakraborty, J.; Singh, R.; Dutta, D.; Naskar, A.; Rajamma, U.; Mohanakumar, K.P. Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-nitropropionic acid-induced rat model of Huntington’s disease. CNS Neurosci. Ther. 2014, 20, 10–19. [Google Scholar] [CrossRef]
  131. Joshi, V.; Mishra, R.; Upadhyay, A.; Amanullah, A.; Poluri, K.M.; Singh, S.; Kumar, A.; Mishra, A. Polyphenolic flavonoid (Myricetin) upregulated proteasomal degradation mechanisms: Eliminates neurodegenerative proteins aggregation. J. Cell. Physiol. 2019, 234, 20900–20914. [Google Scholar] [CrossRef] [PubMed]
  132. Khan, E.; Tawani, A.; Mishra, S.K.; Verma, A.K.; Upadhyay, A.; Kumar, M.; Sandhir, R.; Mishra, A.; Kumar, A. Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington’s Disease (HD) and Spino Cerebellar Ataxia (SCAs). ACS Chem. Biol. 2018, 13, 180–188. [Google Scholar] [CrossRef]
  133. Thangarajan, S.; Ramachandran, S.; Krishnamurthy, P. Chrysin exerts neuroprotective effects against 3-Nitropropionic acid induced behavioral despair—Mitochondrial dysfunction and striatal apoptosis via upregulating Bcl-2 gene and downregulating Bax—Bad genes in male wistar rats. Biomed. Pharmacother. 2016, 84, 514–525. [Google Scholar] [CrossRef]
  134. Haider, M.; Salman, M.; Kaushik, P.; Bharadwaj, N.; Aggarwal, N.B.; Tabassum, H.; Parvez, S. Chrysin ameliorates 3 nitropropinoic acid induced neurotoxicity targeting behavioural, biochemical and histological alterations. Int. J. Neurosci. 2020, 1–9. [Google Scholar] [CrossRef]
  135. Alarcón-Herrera, N.; Flores-Maya, S.; Bellido, B.; García-Bores, A.M.; Mendoza, E.; Ávila-Acevedo, G.; Hernández-Echeagaray, E. Protective effects of chlorogenic acid in 3-nitropropionic acid induced toxicity and genotoxicity. Food Chem. Toxicol. 2017, 109, 1018–1025. [Google Scholar] [CrossRef]
  136. Ip, P.; Sharda, P.R.; Cunningham, A.; Chakrabartty, S.; Pande, V.; Chakrabartty, A. Quercitrin and quercetin 3-β-d-glucoside as chemical chaperones for the A4V SOD1 ALS-causing mutant. Protein Eng. Des. Sel. 2017, 30, 431–440. [Google Scholar] [CrossRef] [PubMed]
  137. Bhatia, N.K.; Modi, P.; Sharma, S.; Deep, S. Quercetin and Baicalein Act as Potent Antiamyloidogenic and Fibril Destabilizing Agents for SOD1 Fibrils. ACS Chem. Neurosci. 2020, 11, 1129–1138. [Google Scholar] [CrossRef] [PubMed]
  138. Ueda, T.; Inden, M.; Shirai, K.; Sekine, S.I.; Masaki, Y.; Kurita, H.; Ichihara, K.; Inuzuka, T.; Hozumi, I. The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity. Sci. Rep. 2017, 7, 2882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Ueda, T.; Inden, M.; Kiuchi, M.; Asaka, Y.; Kurita, H.; Hozumi, I. The effects of kaempferol against mutant copper-zinc superoxide dismutase-mediated toxicity via autophagy. In Proceedings of the Annual Meeting of the Japanese Pharmacological Society WCP2018 (The 18th World Congress of Basic and Clinical Pharmacology), Kyoto, Japan, 1–6 July 2018. [Google Scholar]
  140. Ueda, T.; Ito, T.; Kurita, H.; Inden, M.; Hozumi, I. p-Coumaric acid has protective effects against mutant copper–zinc superoxide dismutase 1 via the activation of autophagy in N2a cells. Int. J. Mol. Sci. 2019, 20, 2942. [Google Scholar] [CrossRef] [Green Version]
  141. Maya, S.; Prakash, T.; Goli, D. Evaluation of neuroprotective effects of wedelolactone and gallic acid on aluminium-induced neurodegeneration: Relevance to sporadic amyotrophic lateral sclerosis. Eur. J. Pharmacol. 2018, 835, 41–51. [Google Scholar] [CrossRef]
  142. Maya, S.; Prakash, T.; Goli Daya, S. Effect of wedelolactone and gallic acid on quinolinic acid-induced neurotoxicity and impaired motor function: Significance to sporadic amyotrophic lateral sclerosis. Neurotoxicology 2018, 68, 1–12. [Google Scholar]
  143. Aaron, C.; Beaudry, G.; Parker, J.A.; Therrien, M. Maple Syrup Decreases TDP-43 Proteotoxicity in a Caenorhabditis elegans Model of Amyotrophic Lateral Sclerosis (ALS). J. Agric. Food Chem. 2016, 64, 3338–3344. [Google Scholar] [CrossRef]
  144. Wu, D.; Zheng, Z.; Fan, S.; Wen, X.; Han, X.; Wang, S.; Wang, Y.; Zhang, Z.; Shan, Q.; Li, M.; et al. Ameliorating effect of quercetin on epilepsy by inhibition of inflammation in glial cells. Exp. Ther. Med. 2020, 20, 854–859. [Google Scholar] [CrossRef]
  145. Moghbelinejad, S.; Rashvand, Z.; Khodabandehloo, F.; Mohammadi, G.; Nassiri-Asl, M. Modulation of the Expression of the GABAA Receptor β1 and β3 Subunits by Pretreatment with Quercetin in the KA Model of Epilepsy in Mice: The Effect of Quercetin on GABAA Receptor Beta Subunits. J. Pharmacopunct. 2016, 19, 163–166. [Google Scholar]
  146. Singh, T.; Kaur, T.; Goel, R.K. Adjuvant quercetin therapy for combined treatment of epilepsy and comorbid depression. Neurochem. Int. 2017, 104, 27–33. [Google Scholar] [CrossRef]
  147. Parihar, G.; Dehariya, B.; Ghule, S.; Dixit, P.; Balekar, N. Quercetin Exerts Anti-convulsant Effects in Animal Model of Grand Mal Epilepsy: Modulation of GABA and Glycinergic Pathways. J. Drug Deliv. Ther. 2017, 7, 194–196. [Google Scholar]
  148. Hashemian, M.; Ghasemi-Kasman, M.; Ghasemi, S.; Akbari, A.; Moalem-Banhangi, M.; Zare, L.; Ahmadian, S.R. Fabrication and evaluation of novel quercetin-conjugated Fe3O4–β-cyclodextrin nanoparticles for potential use in epilepsy disorder. Int. J. Nanomedicine. 2019, 14, 6481. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Sun, Z.Q.; Meng, F.H.; Tu, L.X.; Sun, L. Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF-TrkB signaling pathway and modulating matrix metalloproteinase-9 and GABAA. Exp. Ther. Med. 2019, 17, 3083–3091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Xiang, J.; Jiang, Y. Antiepileptic potential of matrine via regulation the levels of gamma-aminobutyric acid and glutamic acid in the brain. Int. J. Mol. Sci. 2013, 14, 23751–23761. [Google Scholar] [CrossRef] [Green Version]
  151. Zhen, J.L.; Chang, Y.N.; Qu, Z.Z.; Fu, T.; Liu, J.Q.; Wang, W.P. Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling. Epilepsy Behav. 2016, 57, 177–184. [Google Scholar] [CrossRef]
  152. Tambe, R.; Patil, A.; Jain, P.; Sancheti, J.; Somani, G.; Sathaye, S. Assessment of luteolin isolated from Eclipta alba leaves in animal models of epilepsy. Pharm. Biol. 2017, 55, 264–268. [Google Scholar] [CrossRef] [Green Version]
  153. Zhen, J.; Chang, Y.; Tao, F.U.; Zhenzhen, Q.U.; Liu, J.; Wang, W. Effects of luteolin on CaM-CaMPK signaling pathway in hippocampus in epileptic rats. Int. J. Tradit. Chin. Med. 2016, 38, 232–237. [Google Scholar]
  154. Sharma, P.; Kumari, A.; Gulati, A.; Krishnamurthy, S.; Hemalatha, S. Chrysin isolated from Pyrus pashia fruit ameliorates convulsions in experimental animals. Nutr. Neurosci. 2019, 22, 569–577. [Google Scholar] [CrossRef]
  155. Zhang, Y.; Zhao, J.; Afzal, O.; Kazmi, I.; Al-Abbasi, F.A.; Altamimi, A.S.A.; Yang, Z. Neuroprotective role of chrysin-loaded poly (lactic-co-glycolic acid) nanoparticle against kindling-induced epilepsy through Nrf2/ARE/HO-1 pathway. J. Biochem. Mol. Toxicol. 2020, 35, e22634. [Google Scholar] [CrossRef]
  156. Hashemi, P.; Babaei, J.F.; Vazifekhah, S.; Nikbakht, F. Evaluation of the neuroprotective, anticonvulsant, and cognition-improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway. Iran. J. Basic Med. Sci. 2019, 22, 752. [Google Scholar]
  157. Zhang, Y.; Seeburg, D.P.; Pulli, B.; Wojtkiewicz, G.R.; Bure, L.; Atkinson, W.; Schob, S.; Iwamoto, Y.; Ali, M.; Zhang, W.; et al. Myeloperoxidase nuclear imaging for epileptogenesis. Radiology 2016, 278, 822–830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Shao, C.; Yuan, J.; Liu, Y.; Qin, Y.; Wang, X.; Gu, J.; Chen, G.; Zhang, B.; Liu, H.K.; Zhao, J.; et al. Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis. Proc. Natl. Acad. Sci. USA 2020, 117, 10155–10164. [Google Scholar] [CrossRef] [PubMed]
  159. Sharma, P.; Sharma, S.; Singh, D. Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus. Nutr. Neurosci. 2020, 23, 118–127. [Google Scholar] [CrossRef] [PubMed]
  160. Singh, T.; Kaur, T.; Goel, R.K. Ferulic Acid Supplementation for management of depression in epilepsy. Neurochem. Res. 2017, 42, 2940–2948. [Google Scholar] [CrossRef] [PubMed]
  161. Hussein, A.M.; Abbas, K.M.; Abulseoud, O.A.; El-Hussainy, E.M.A. Effects of ferulic acid on oxidative stress, heat shock protein 70, connexin 43, and monoamines in the hippocampus of pentylenetetrazole-kindled rats. Can. J. Physiol. Pharmacol. 2017, 95, 732–742. [Google Scholar] [CrossRef]
  162. Hassanzadeh, P.; Arbabi, E.; Atyabi, F.; Dinarvand, R. Ferulic acid exhibits antiepileptogenic effect and prevents oxidative stress and cognitive impairment in the kindling model of epilepsy. Life Sci. 2017, 179, 9–14. [Google Scholar] [CrossRef]
  163. Zhang, S.H.; Liu, D.; Hu, Q.; Zhu, J.; Wang, S.; Zhou, S. Ferulic acid ameliorates pentylenetetrazol-induced seizures by reducing neuron cell death. Epilepsy Res. 2019, 156, 106183. [Google Scholar] [CrossRef]
  164. Shakeel, S.; Rehman, M.U.; Tabassum, N.; Amin, U. Effect of naringenin (a naturally occurring flavanone) against pilocarpine-induced status epilepticus and oxidative stress in mice. Pharmacogn. Mag. 2017, 13 (Suppl. S1), S154–S160. [Google Scholar]
  165. Park, J.; Jeong, K.H.; Shin, W.H.; Bae, Y.S.; Jung, U.J.; Kim, S.R. Naringenin ameliorates kainic acid-induced morphological alterations in the dentate gyrus in a mouse model of temporal lobe epilepsy. Neuroreport 2016, 27, 1182–1189. [Google Scholar] [CrossRef]
  166. Khodayar, M.J.; Salehi, S.; Rezaei, M.; Siahpoosh, A.; Khazaei, A.; Houshmand, G. Evaluation of the effect of naringenin on pentylenetetrazole and maximal electroshock-induced convulsions in mice. Jundishapur J. Nat. Pharm. Prod. 2017, 12, e31384. [Google Scholar]
  167. Mert, D.G.; Turgut, N.H.; Arslanbas, E.; Gungor, H.; Kara, H. The influence of quercetin on recognition memory and brain oxidative damage in a ketamine model of schizophrenia. Psychiatry Clin. Psychopharmacol. 2019, 29, 1–7. [Google Scholar] [CrossRef] [Green Version]
  168. Hajizadeh, M.A.; Valizadegan, F. Antidepressant effects of quercetin and its nanocrystal on schizophrenia animal model with using forced swimming test. J. Anim. Res. 2017, 30, 365–376. [Google Scholar]
  169. Hosseiny, R.; Hajizadeh, M.A.; Zare, M.; Mermohammad, R.F. The effect of quercetin and its nanocrystalin on behavioral impairment induced by ketamine injection in an animal model of schizophrenia. Daneshvar Med. 2016, 23, 11–20. [Google Scholar]
  170. Schwartz, D.L. Quercetin as an Augmentation Agent in Schizophrenia. J. Clin. Psychopharmacol. 2016, 36, 282–283. [Google Scholar] [CrossRef]
  171. Samad, N.; Saleem, A.; Yasmin, F.; Shehzad, M.A. Quercetin protects against stress-induced anxiety- and depression-like behavior and improves memory in male mice. Physiol. Res. 2018, 67, 795–808. [Google Scholar] [CrossRef]
  172. Khan, K.; Najmi, A.K.; Akhtar, M. A natural phenolic compound quercetin showed the usefulness by targeting inflammatory, oxidative stress markers and augment 5-HT levels in one of the animal models of depression in mice. Drug Res. 2019, 69, 392–400. [Google Scholar] [CrossRef]
  173. Fang, K.; Li, H.R.; Chen, X.X.; Gao, X.R.; Huang, L.L.; Du, A.Q.; Jiang, C.; Li, H.; Ge, J.F. Quercetin Alleviates LPS-Induced Depression-Like Behavior in Rats via Regulating BDNF-Related Imbalance of Copine 6 and TREM1/2 in the Hippocampus and PFC. Front. Pharmacol. 2020, 10, 1544. [Google Scholar] [CrossRef]
  174. Ma, Z.; Wang, G.; Cui, L.; Wang, Q. Myricetin attenuates depressant-like behavior in mice subjected to repeated restraint stress. Int. J. Mol. Sci. 2015, 16, 28377–28385. [Google Scholar] [CrossRef] [Green Version]
  175. Wang, Q.M.; Wang, G.L.; Ma, Z.G. Protective effects of myricetin on chronic stress-induced cognitive deficits. Neuroreport 2016, 27, 652–658. [Google Scholar] [CrossRef]
  176. Gao, W.; Wang, W.; Peng, Y.; Deng, Z. Antidepressive effects of kaempferol mediated by reduction of oxidative stress, proinflammatory cytokines and up-regulation of AKT/β-catenin cascade. Metab. Brain Dis. 2019, 34, 485–494. [Google Scholar] [CrossRef]
  177. Filho, C.B.; Jesse, C.R.; Donato, F.; Giacomeli, R.; Del Fabbro, L.; da Silva Antunes, M.; de Gomes, M.G.; Goes, A.T.; Boeira, S.P.; Prigol, M.; et al. Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+, K+-ATPase activity in the hippocampus and prefrontal cortex of mice: Antidepressant effect of chrysin. Neuroscience 2015, 289, 367–380. [Google Scholar] [CrossRef] [PubMed]
  178. Borges Filho, C.; Jesse, C.R.; Donato, F.; Del Fabbro, L.; de Gomes, M.G.; Goes, A.T.; Souza, L.C.; Boeira, S.P. Chrysin promotes attenuation of depressive-like behavior and hippocampal dysfunction resulting from olfactory bulbectomy in mice. Chem. Biol. Interact. 2016, 260, 154–162. [Google Scholar] [CrossRef] [PubMed]
  179. Bansal, Y.; Singh, R.; Saroj, P.; Sodhi, R.K.; Kuhad, A. Naringenin protects against oxido-inflammatory aberrations and altered tryptophan metabolism in olfactory bulbectomized-mice model of depression. Toxicol. Appl. Pharmacol. 2018, 355, 257–268. [Google Scholar] [CrossRef] [PubMed]
  180. Umukoro, S.; Kalejaye, H.A.; Ben-Azu, B.; Ajayi, A.M. Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. Biomed. Pharmacother. 2018, 105, 714–723. [Google Scholar] [CrossRef]
  181. Tayyab, M.; Farheen, S.; Khanam, N.; Mobarak Hossain, M.; Shahi, M.H. Antidepressant and Neuroprotective Effects of Naringenin via Sonic Hedgehog-GLI1 Cell Signaling Pathway in a Rat Model of Chronic Unpredictable Mild Stress. Neuromolecular. Med. 2019, 21, 250–261. [Google Scholar] [CrossRef]
  182. Lee, S.; Kim, H.B.; Hwang, E.S.; Kim, E.S.; Kim, S.S.; Jeon, T.D.; Song, M.C.; Lee, J.S.; Chung, M.C.; Maeng, S.; et al. Antidepressant-like Effects of p-Coumaric Acid on LPS-induced Depressive and Inflammatory Changes in Rats. Exp. Neurobiol. 2018, 27, 189–199. [Google Scholar] [CrossRef]
  183. Zheng, X.; Cheng, Y.; Chen, Y.; Yue, Y.; Li, Y.; Xia, S.; Li, Y.; Deng, H.; Zhang, J.; Cao, Y. Ferulic acid improves depressive-like behavior in prenatally stressed offspring rats via anti-inflammatory activity and HPA axis. Int. J. Mol. Sci. 2019, 20, 493. [Google Scholar] [CrossRef] [Green Version]
  184. Bo, X.M.; Yu, R.B.; Du, S.J.; Zhang, R.L.; He, L. Ferulic acid alleviates lipopolysaccharide-induced depression-like behavior by inhibiting inflammation and apoptosis. Asian Pac. J. Trop. Biomed. 2020, 10, 523. [Google Scholar]
  185. Zhao, L.; Zhu, L.; Guo, X. Valproic acid attenuates Aβ25-35-induced neurotoxicity in PC12 cells through suppression of mitochondria-mediated apoptotic pathway. Biomed. Pharmacother. 2018, 106, 77–82. [Google Scholar] [CrossRef]
  186. Ahmad, L.; Mujahid, M.; Mishra, A.; Rahman, M.A. Protective role of hydroalcoholic extract of Cajanus cajan Linn leaves against memory impairment in sleep deprived experimental rats. J. Ayurveda. Integr. Med. 2020, 11, 471–477. [Google Scholar] [CrossRef]
  187. Zhang, L.; Xia, R.; Jia, J.; Wang, L.; Li, K.; Li, Y.; Zhang, J. Oleanolic acid protects against cognitive decline and neuroinflammation-mediated neurotoxicity by blocking secretory phospholipase A2 IIA-activated calcium signals. Mol. Immunol. 2018, 99, 95–103. [Google Scholar] [CrossRef] [PubMed]
  188. Ali, A.A.; Abo El-Ella, D.M.; El-Emam, S.Z.; Shahat, A.S.; El-Sayed, R.M. Physical & mental activities enhance the neuroprotective effect of vinpocetine & coenzyme Q10 combination against Alzheimer & bone remodeling in rats. Life Sci. 2019, 229, 21–35. [Google Scholar] [PubMed]
  189. Yuan, H.; Jiang, C.; Zhao, J.; Zhao, Y.; Zhang, Y.; Xu, Y.; Gao, X.; Guo, L.; Liu, Y.; Liu, K.; et al. Euxanthone Attenuates Aβ1-42-Induced Oxidative Stress and Apoptosis by Triggering Autophagy. J. Mol. Neurosci. 2018, 66, 512–523. [Google Scholar] [CrossRef] [PubMed]
  190. Aminyavari, S.; Zahmatkesh, M.; Farahmandfar, M.; Khodagholi, F.; Dargahi, L.; Zarrindast, M.R. Protective role of Apelin-13 on amyloid β25–35-induced memory deficit; involvement of autophagy and apoptosis process. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2019, 89, 322–334. [Google Scholar] [CrossRef]
  191. Aykac, A.; Ozbeyli, D.; Uncu, M.; Ertaş, B.; Kılınc, O.; Şen, A.; Orun, O.; Sener, G. Evaluation of the protective effect of Myrtus communis in scopolamine-induced Alzheimer model through cholinergic receptors. Gene 2019, 689, 194–201. [Google Scholar] [CrossRef]
  192. Ali, A.M.; Kunugi, H. Bee honey protects astrocytes against oxidative stress: A preliminary in vitro investigation. Neuropsychopharmacol. Rep. 2019, 39, 312–314. [Google Scholar] [CrossRef] [Green Version]
  193. Arranz, A.M.; De Strooper, B. The role of astroglia in Alzheimer’s disease: Pathophysiology and clinical implications. Lancet Neurol. 2019, 18, 406–414. [Google Scholar] [CrossRef]
  194. Baranowska-Wójcik, E.; Szwajgier, D.; Winiarska-Mieczan, A. Honey as the potential natural source of cholinesterase inhibitors in Alzheimer’s disease. Plant Foods Hum. Nutr. 2020, 75, 30–32. [Google Scholar] [CrossRef]
  195. Şahin, B. Can sunflower honey have a protective effect against Alzheimer’s disease? J. Ongoing Chem. Res. 2021, 6, 6–9. [Google Scholar]
  196. Shati, A.A.; Elsaid, F.G.; Hafez, E.E. Biochemical and molecular aspects of aluminium chloride-induced neurotoxicity in mice and the protective role of Crocus sativus L. extraction and honey syrup. Neuroscience 2011, 175, 66–74. [Google Scholar] [CrossRef]
  197. Saxena, A.K.; Phyu, H.P.; Al-Ani, I.M.; Talib, N.A. Potential protective effect of honey against chronic cerebral hypoperfusion-induced neurodegeneration in rats. J. Anat. Soc. India 2014, 63, 151–155. [Google Scholar] [CrossRef]
  198. Cheng, W.; Chen, W.; Wang, P.; Chu, J. Asiatic acid protects differentiated PC12 cells from Aβ25–35-induced apoptosis and tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β signaling. Life Sci. 2018, 208, 96–101. [Google Scholar] [CrossRef] [PubMed]
  199. Fawzy Fahim, V.; Wadie, W.; Shafik, A.N.; Ishak Attallah, M. Role of simvastatin and insulin in memory protection in a rat model of diabetes mellitus and dementia. Brain. Res. Bull. 2019, 144, 21–27. [Google Scholar] [CrossRef] [PubMed]
  200. Klein, C.P.; Hoppe, J.B.; Saccomori, A.B.; Dos Santos, B.G.; Sagini, J.P.; Crestani, M.S.; August, P.M.; Hözer, R.M.; Grings, M.; Parmeggiani, B.; et al. Physical exercise during pregnancy prevents cognitive impairment induced by amyloid-β in adult offspring rats. Mol. Neurobiol. 2019, 56, 2022–2038. [Google Scholar] [CrossRef]
  201. Liu, Y.; Zhang, P.; Zheng, Y.; Yang, C.; Du, T.; Ge, M.; Chang, X.; Duan, R.; Ma, G. Effects of NMDAR Antagonist on the Regulation of P-MARCKS Protein to Aβ1-42 Oligomers Induced Neurotoxicity. Neurochem. Res. 2018, 43, 2008–2015. [Google Scholar] [CrossRef]
  202. Altenhöfer, S.; Witte, I.; Teiber, J.F.; Wilgenbus, P.; Pautz, A.; Li, H.; Daiber, A.; Witan, H.; Clement, A.M.; Förstermann, U.; et al. One enzyme, two functions pon2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity. J. Biol. Chem. 2010, 285, 24398–24403. [Google Scholar] [CrossRef] [Green Version]
  203. Cardoso, S.M.; Moreira, P.I.; Agostinho, P.; Pereira, C.; Oliveira, C.R. Neurodegenerative pathways in Parkinson’s disease: Therapeutic strategies. Curr. Drug Targets CNS Neurol. Disord. 2005, 4, 405–419. [Google Scholar] [CrossRef] [Green Version]
  204. Schapira, A.H. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008, 7, 97–109. [Google Scholar] [CrossRef]
  205. Shim, J.S.; Kim, H.G.; Ju, M.S.; Choi, J.G.; Jeong, S.Y.; Oh, M.S. Effects of the hook of Uncaria rhynchophylla on neurotoxicity in the 6-hydroxydopamine model of Parkinson’s disease. J. Ethnopharmacol. 2009, 126, 361–365. [Google Scholar] [CrossRef]
  206. Chaudhuri, K.R.; Schapira, A.H. Non-motor symptoms of Parkinson’s disease: Dopaminergic pathophysiology and treatment. Lancet Neurol. 2009, 8, 464–474. [Google Scholar] [CrossRef]
  207. Martin, L.J. Mitochondrial and cell death mechanisms in neurodegenerative diseases. Pharmaceuticals 2010, 3, 839–915. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Cheng, F.; Vivacqua, G.; Yu, S. The role of α-synuclein in neurotransmission and synaptic plasticity. J. Chem. Neuroanat. 2011, 42, 242–248. [Google Scholar] [CrossRef] [PubMed]
  209. Kalia, L.V.; Lang, A.E. Parkinson’s disease. Lancet 2015, 386, 896–912. [Google Scholar] [CrossRef]
  210. In, S.; Hong, C.W.; Choi, B.; Jang, B.G.; Kim, M.J. Inhibition of mitochondrial clearance and Cu/Zn-SOD activity enhance 6-hydroxydopamine-induced neuronal apoptosis. Mol. Neurobiol. 2016, 53, 777–791. [Google Scholar] [CrossRef] [PubMed]
  211. Sarrafchi, A.; Bahmani, M.; Shirzad, H.; Rafieian-Kopaei, M. Oxidative stress and Parkinson’s disease: New hopes in treatment with herbal antioxidants. Curr. Pharm. Des. 2016, 22, 238–246. [Google Scholar] [CrossRef] [Green Version]
  212. Yildiz, O.K.T.A.Y.; Karahalil, F.A.T.M.A.; Can, Z.; Sahin, H.; Kolayli, S.E.V.G.İ. Total monoamine oxidase (MAO) inhibition by chestnut honey, pollen and propolis. J. Enzym. Inhib. Med. Chem. 2014, 29, 690–694. [Google Scholar] [CrossRef]
  213. Topal, N.; Bulduk, I.; Mut, Z.; Bozoğlu, H.; Tosun, Y.K. Flowers, Pollen and Honey for Use in the Treatment of Parkinson’s Disease. Rev. Chim. 2020, 71, 308–319. [Google Scholar] [CrossRef]
  214. Vonsattel, J.P.; DiFiglia, M. Huntington disease. J. Neuropathol. Exp. Neurol. 1998, 57, 369–384. [Google Scholar] [CrossRef] [Green Version]
  215. Wexler, A.; Wild, E.J.; Tabrizi, S.J. George Huntington: A legacy of inquiry, empathy and hope. Brain 2016, 139 Pt 8, 2326–2333. [Google Scholar] [CrossRef] [Green Version]
  216. McColgan, P.; Tabrizi, S.J. Huntington’s disease: A clinical review. Eur. J. Neurol. 2018, 25, 24–34. [Google Scholar] [CrossRef]
  217. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 1993, 72, 971–983.
  218. Jin, Y.N.; Johnson, G.V. The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease. J. Bioenerg. Biomembr. 2010, 42, 199–205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Van Es, M.A.; Hardiman, O.; Chio, A.; Al-Chalabi, A.; Pasterkamp, R.J.; Veldink, J.H.; van den Berg, L.H. Amyotrophic lateral sclerosis. Lancet 2017, 390, 2084–2098. [Google Scholar] [CrossRef]
  220. Hardiman, O.; Al-Chalabi, A.; Chio, A.; Corr, E.M.; Logroscino, G.; Robberecht, W.; Shaw, P.J.; Simmons, Z.; van den Berg, L.H. Amyotrophic lateral sclerosis. Nat. Rev. Dis. Primers. 2017, 3, 17085. [Google Scholar] [CrossRef] [PubMed]
  221. Brown, R.H.; Al-Chalabi, A. Amyotrophic Lateral Sclerosis. N. Engl. J. Med. 2017, 377, 162–172. [Google Scholar] [CrossRef] [Green Version]
  222. Bond, L.; Bernhardt, K.; Madria, P.; Sorrentino, K.; Scelsi, H.; Mitchell, C.S. A Metadata Analysis of Oxidative Stress Etiology in Preclinical Amyotrophic Lateral Sclerosis: Benefits of Antioxidant Therapy. Front. Neurosci. 2018, 12, 10. [Google Scholar] [CrossRef] [Green Version]
  223. Massey, L.K.; Mah, A.L.; Ford, D.L.; Miller, J.; Liang, J.; Doong, H.; Monteiro, M.J. Overexpression of ubiquilin decreases ubiquitination and degradation of presenilin proteins. J. Alzheimer’s Dis. 2004, 6, 79–92. [Google Scholar] [CrossRef]
  224. Phokasem, P.; Jantrapirom, S.; Karinchai, J.; Yoshida, H.; Yamaguchi, M.; Chantawannakul, P. Honeybee products and edible insect powders improve locomotive and learning abilities of Ubiquilin-knockdown Drosophila. BMC Complement. Med. Ther. 2020, 20, 267. [Google Scholar] [CrossRef]
  225. Thijs, R.D.; Surges, R.; O’Brien, T.J.; Sander, J.W. Epilepsy in adults. Lancet 2019, 393, 689–701. [Google Scholar] [CrossRef]
  226. Beghi, E. The Epidemiology of Epilepsy. Neuroepidemiology 2020, 54, 185–191. [Google Scholar] [CrossRef]
  227. Hashemian, M.; Anissian, D.; Ghasemi-Kasman, M.; Akbari, A.; Khalili-Fomeshi, M.; Ghasemi, S.; Ahmadi, F.; Moghadamnia, A.A.; Ebrahimpour, A. Curcumin-loaded chitosan-alginate-STPP nanoparticles ameliorate memory deficits and reduce glial activation in pentylenetetrazol-induced kindling model of epilepsy. Prog. Neuropsychopharmacol. Biol. Psychiatry 2017, 79, 462–471. [Google Scholar] [CrossRef] [PubMed]
  228. Nieoczym, D.; Socała, K.; Raszewski, G.; Wlaź, P. Effect of quercetin and rutin in some acute seizure models in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 54, 50–58. [Google Scholar] [CrossRef] [PubMed]
  229. Garlich, F.M.; Balakrishnan, K.; Shah, S.K.; Howland, M.A.; Fong, J.; Nelson, L.S. Prolonged altered mental status and bradycardia following pediatric donepezil ingestion. Clin. Toxicol. 2014, 52, 291–294. [Google Scholar] [CrossRef] [PubMed]
  230. Nair, A.; Vaidya, V.A. Cyclic AMP response element binding protein and brain-derived neurotrophic factor: Molecules that modulate our mood? J. Biosci. 2006, 31, 423–434. [Google Scholar] [CrossRef] [Green Version]
  231. Jiang, D.G.; Jin, S.L.; Li, G.Y.; Li, Q.Q.; Li, Z.R.; Ma, H.X.; Zhuo, C.J.; Jiang, R.H.; Ye, M.J. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress. Neural Regen. Res. 2016, 11, 1471. [Google Scholar]
  232. Yu, L.; Zhang, Y.; Ma, R.; Bao, L.; Fang, J.; Yu, T. Potent protection of ferulic acid against excitotoxic effects of maternal intragastric administration of monosodium glutamate at a late stage of pregnancy on developing mouse fetal brain. Eur. Neuropsychopharmacol. 2006, 16, 170–177. [Google Scholar] [CrossRef]
  233. Xie, W.; Cai, L.; Yu, Y.; Gao, L.; Xiao, L.; He, Q.; Ren, Z.; Liu, Y. Activation of brain indoleamine 2,3-dioxygenase contributes to epilepsy-associated depressive-like behavior in rats with chronic temporal lobe epilepsy. J. Neuroinflamm. 2014, 11, 41. [Google Scholar] [CrossRef] [Green Version]
  234. Waldbaum, S.; Patel, M. Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy? J. Bioenerg. Biomembr. 2010, 42, 449–455. [Google Scholar] [CrossRef] [Green Version]
  235. Na, M.; Liu, Y.; Shi, C.; Gao, W.; Ge, H.; Wang, Y.; Wang, H.; Long, Y.; Shen, H.; Shi, C.; et al. Prognostic value of CA4/DG volumetry with 3 T magnetic resonance imaging on postoperative outcome of epilepsy patients with dentate gyrus pathology. Epilepsy Res. 2014, 108, 1315–1325. [Google Scholar] [CrossRef]
  236. Schultz, S.H.; North, S.W.; Shields, C.G. Schizophrenia: A review. Am. Fam. Physician. 2007, 75, 1821–1829. [Google Scholar]
  237. Lewis, D.A.; Lieberman, J.A. Catching up on schizophrenia: Natural history and neurobiology. Neuron 2000, 28, 325–334. [Google Scholar] [CrossRef] [Green Version]
  238. Magalhães, P.V.; Dean, O.; Andreazza, A.C.; Berk, M.; Kapczinski, F. Antioxidant treatments for schizophrenia. Cochrane Database Syst. Rev. 2016, 10, CD008919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  239. Mahadik, S.P.; Mukherjee, S. Free radical pathology and antioxidant defense in schizophrenia: A review. Schizophr. Res. 1996, 19, 1–17. [Google Scholar] [CrossRef]
  240. Yahaya, R.; Zahary, M.N.; Othman, Z.; Ismail, R.; Him, N.A.S.N.; Abd Aziz, A.; Dahlan, R.; Jusoh, A.F. Tualang honey supplementation as cognitive enhancer in patients with schizophrenia. Heliyon 2020, 6, e03948. [Google Scholar] [CrossRef] [PubMed]
  241. Perez-Caballero, L.; Torres-Sanchez, S.; Romero-López-Alberca, C.; González-Saiz, F.; Mico, J.A.; Berrocoso, E. Monoaminergic system and depression. Cell Tissue Res. 2019, 377, 107–113. [Google Scholar] [CrossRef]
  242. Racagni, G.; Popoli, M. The pharmacological properties of antidepressants. Int. Clin. Psychopharmacol. 2010, 25, 117–131. [Google Scholar] [CrossRef]
  243. Schildkraut, J.J.; Kety, S.S. Biogenic amines and emotion. Science 1967, 156, 21–37. [Google Scholar] [CrossRef]
  244. Dell’Osso, L.; Carmassi, C.; Mucci, F.; Marazziti, D. Depression, Serotonin and Tryptophan. Curr. Pharm. Des. 2016, 22, 949–954. [Google Scholar] [CrossRef]
  245. Nautiyal, K.M.; Hen, R. Serotonin receptors in depression: From A to B. F1000Research 2017, 6, 123. [Google Scholar] [CrossRef] [Green Version]
  246. Raison, C.L.; Capuron, L.; Miller, A.H. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol. 2006, 27, 24–31. [Google Scholar] [CrossRef] [Green Version]
  247. Duman, R.S.; Deyama, S.; Fogaça, M.V. Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur. J. Neurosci. 2019, 53, 126–139. [Google Scholar] [CrossRef] [PubMed]
  248. Beurel, E.; Toups, M.; Nemeroff, C.B. The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Neuron 2020, 107, 234–256. [Google Scholar] [CrossRef] [PubMed]
  249. Maes, M.; Galecki, P.; Chang, Y.S.; Berk, M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro) degenerative processes in that illness. Prog. NeuroPsychopharmacol. Biol. Psychiatry 2011, 35, 676–692. [Google Scholar] [PubMed]
  250. Bakunina, N.; Pariante, C.M.; Zunszain, P.A. Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 2015, 144, 365–373. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  251. Lindqvist, D.; Dhabhar, F.S.; James, S.J.; Hough, C.M.; Jain, F.A.; Bersani, F.S.; Reus, V.I.; Verhoeven, J.E.; Epel, E.S.; Mahan, L.; et al. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 2017, 76, 197–205. [Google Scholar] [CrossRef] [Green Version]
  252. Huang, Q.; Liu, H.; Suzuki, K.; Ma, S.; Liu, C. Linking What We Eat to Our Mood: A Review of Diet, Dietary Antioxidants, and Depression. Antioxidants 2019, 8, 376. [Google Scholar] [CrossRef] [Green Version]
  253. Bhatt, S.; Nagappa, A.N.; Patil, C.R. Role of oxidative stress in depression. Drug Discov. Today 2020, 25, 1270–1276. [Google Scholar] [CrossRef]
  254. Sheas, M.N.; Rasool, H.; Rafique, M.N.; Tariq, M.R.; Muhammad, A.; Ali, K. Exploring the Potential of Honey and Curcumin as Antidepressent. Punjab Univ. J. Zool. 2019, 34, 89–95. [Google Scholar] [CrossRef]
Molecules 27 03297 g001 550
Figure 1. The therapeutic potential of various polyphenols in honey in different neurological disorders. Various types of honey have a wide range of these vital polyphenols, suggesting honey as a potent complementary and alternative medicine for the management and treatment of a variety of neurological diseases.
Figure 1. The therapeutic potential of various polyphenols in honey in different neurological disorders. Various types of honey have a wide range of these vital polyphenols, suggesting honey as a potent complementary and alternative medicine for the management and treatment of a variety of neurological diseases.
Molecules 27 03297 g001
Table
Table 1. Quantity (µg/kg) of Different Polyphenols in Various Types of Honey.
Table 1. Quantity (µg/kg) of Different Polyphenols in Various Types of Honey.
Active
Ingredient		Honey TypeQuantification Method
Manuka
[15,16,17]		Acacia
[18,19]		Eucalyptus
[20]		Chestnut
[21]		Cedar
[22]		Sunflower
[23]		Clover
[24]
Quercetin4320010546-200200HPLC
Myricetin70-780138---UHPLC
Galangin35550-149-220-UPLC
Apigenin4029014010047090260HPLC
Naringenin-60-350107169368RP-HPLC
Chrysin30130190 680170-470UHPLC
Luteolin381406680464320550HPLC-DAD
Pinocembrin180640142--440-HPLC
Pinobanksin290148319----HPLC
Isorhamnetin4090-----HPLC
Kaempferol15090147250670120172HPLC-UV
Gallic acid300101531610354160760HPLC-UV
Caffeic acid50110900997255350772HPLC-UV
Coumaric acid103170101786915110147HPLC-UV
Chlorogenic acid6040284552-360-HPLC-DAD
Ferulic acid-740368166220-531HPLC-PDA
Syringic acid400300366202394-235HPLC-UV
Cinnamic acid-50-45060-570HPLC-UV
Benzoic acid51-870150---HPLC
Total Active
Ingredients		1880384953095706347625395035-
Table
Table 2. Effects of Different Components of Honey in Various Neurological Disorders.
Table 2. Effects of Different Components of Honey in Various Neurological Disorders.
DiseaseComponentEffectReferences
Alzheimer’s DiseaseQuercetinImproves mitochondrial activity[89]
Activates Nrf-2 signaling[90]
Deceases oxidative stress
Reduces oxidative stress via PON2 activity[91]
Reduces neuroinflammation[92,93]
Decreases astrogliosis
Prevents neurodegeneration
Recovers cognitive disabilities
MyricetinImproves memory and cognitive function[94]
Prevents the formation of fibrils as well as oligomers of Aβ[95]
Anti-tau protein effect
↓ Acetylcholinesterase[96]
↑ Acetylcholine
Exhibits anti-inflammatory activity[97,98]
Inhibition of the NF-κB pathway and NLRP3 inflammasome
Prevents the formation of fibrils as well as oligomers of Aβ[99]
KaempferolDecreases lipid peroxidation and senile plaque formation[100]
Protects from apoptotic damage
Regulates concentrations of antioxidative enzymes[101]
↓ TNF-α and inhibits inflammation
Exhibits anti-apoptotic activity[102]
Downregulates Bcl-2-associated X protein (Bax) and cleaved caspase-9
Increases neuronal density in the hippocampus[103]
Downregulates inflammatory proteins[104]
Protects from oxidative damage[105]
LuteolinAlleviates oxidative stress[106]
Scavenges free radicals
Downregulates inflammatory and apoptotic proteins
Improves memory deficits[107]
Maintains neuronal density
GalanginDiminishes autophagy[108]
Decreases levels of p-tau, β-secretase, and Aβ42
↑ Acetylcholine[109]
Improves cognitive functions
Caffeic acid↓ Acetylcholinesterase[110]
↓ Inflammation
↓ Oxidative stress
Cinnamic acidAttenuates the formation of amyloid plaques[111]
Activates PPARα
Improves memory functions
Parkinson’s DiseaseQuercetinProtects from degeneration[112]
↑ Dopamine levels
↑ Brain-Derived Neurotrophic Factor expression
↑ Energy production of mitochondria
Restores activities of antioxidant enzymes[113]
Repairs cognitive deficits
↓ Endoplasmic reticulum stress[114]
↓ C/EBP homologous protein (CHOP)
↑ Autophagy
↑ Beclin-1 expression
Myricetin↓ Degeneration[115]
↑ Dopamine levels
Inhibits inflammation[116]
Prevents the activation of microglia
↓ Expression of inflammatory cytokines
Chrysin↑ Expression of a survival factor MEF2D[117]
Inhibits MAO-B
Alleviates oxidative stress[118]
Prevents inflammation and dysfunction of Na+, K+-ATPase pump
Ameliorates neuronal loss[119]
Improves memory
Ellagic acidInhibits MAO activity[120]
Prevents the loss of neurons
↓ Oxidative stress
Modulates levels of antioxidant enzymes[121]
Protects from oxidative insult
Diminishes apoptosis[122]
Inhibits MAO-B
Modulates ERβ/Nrf2/HO-1 signaling cascade
Cinnamic acidProtects neurodegeneration[123]
Activates Peroxisome Proliferator Activating Receptor α (PPARα)
GalanginInhibits microglial activation[124]
Suppresses inflammatory factors
Activates PPAR-γ[125,126,127]
Inhibits inflammation
Prevents apoptosis
Protects from oxidative damage
ApigeninExhibits antioxidative function[128]
Inhibits MAO
Prevents apoptosis
Inhibits caspase-3 activation
Huntington’s DiseaseQuercetinImproves motor functions[129]
Regulates peroxisome proliferator-activated receptor gamma, coactivator (PGC-1), or sirtuins (SIRT1)
↑ Energy production of mitochondria
Ameliorates behavioral malfunctions[130]
Exhibits anxiolytic effect
MyricetinReduces aggregation of polyglutamine[131]
↓ Proteo toxicity[132]
Repairs behavioral changes
ChrysinUpregulates anti-apoptotic factor[133]
Downregulates pro-apoptotic factor
Restores neurobehavioral functions[134]
↑ Serotonin
Chlorogenic acidProtects from genotoxicity[135]
Amyotrophic Lateral SclerosisQuercetinInhibits aggregation of Cu-Zn superoxide dismutase (SOD)[136,137]
KaempferolPrevents cell death[138,139]
Reduces aggregation of superoxide dismutase 1 (SOD1)
↑ AMPK phosphorylation
Inhibits mTOR phosphorylation
Boosts up autophagy
Coumaric acidAmeliorates oxidative stress and endoplasmic reticulum stress[140]
↑ Autophagy
Gallic acid↑ Levels of antioxidant enzymes[141]
↓ Lipid peroxidation
Downregulates inflammatory cytokines such as TNF-α, IL-6, IL-β, and NF-κB
Improves motor functions
Prevents glutamate excitotoxicity[142]
Inhibits the formation of neurofibrillary tangles
Improves motor skills
↓ TDP-43 proteotoxicity[143]
Attenuates seizures
EpilepsyQuercetinInhibits activation of microglial cells and inflammatory cytokines[144]
Attenuates neurodegeneration
Inhibits expression of the gene for GABA receptors[145]
Reduces depression
Restores tryptophan levels[146]
Exerts anticonvulsant effect
Modulates Glycinergic and GABAergic ion channels[147]
Reduces behavioral signs of seizures
↓ Neuronal loss[148]
↓ Astrocyte activation
MyricetinAmeliorates intensity of seizures[149,150]
Inhibits apoptosis
Downregulates Bad, Bax, and cleaved caspase 3
Upregulates Bcl-2 and Bcl-xL
Normalizes glutamate/GABA
LuteolinImproves cognitive deficits[151]
↑ Expression of Brain-Derived Neurotrophic Factor (BDNF)
Exhibits anticonvulsant effect[152]
↑ Activation of receptors for GABAA
Reduces oxidative stress
Improves cognition impairments[153]
Modulates CaM-CaMPK signaling pathway
Attenuates seizures
ChrysinModulates GABAA receptors[154]
Abrogates convulsion-induced oxidative damage
↓ The severity of epileptic seizures[155]
↓ Apoptosis
Boosts the expression of Nrf2, NQO-1, and HO-1
ApigeninReduces neuronal loss[156]
↓ Release of cytochrome c from mitochondria
Alleviates apoptosis
Inhibits overexpression of hypochlorite (HClO)[157,158]
↓ Oxidative damage
Averts cognitive impairments[159]
Exerts antidepressant and anti-anxiolytic effects
↑ Expression of Brain-Derived Neurotrophic Factor (BDNF)
Ferulic acidPalliates depression[160]
↓ Levels of proinflammatory cytokines such as TNF-α and IL-1β
Inhibits Cyclooxygenase 2 (COX2) activity
Modulates corticosterone levels
Ameliorates oxidative stress[161]
Upregulates neuroprotective Heat shock protein 70 (Hsp70) and neurotransmitters such as Serotonin (5-HT) and norepinephrine
Diminishes oxidative stress[162]
Repairs cognitive deficits and seizure activity
Improves memory functions and learning capacities[163]
Inhibits apoptotic process
Scavenges free radicles
Naringenin↑ Antioxidant enzymes[164]
Restores neuronal morphology
↓ Neurodegeneration
Impedes occurrence of seizures[165]
↓ Granule cell disruption (GCD) in the hippocampus
Ameliorates generation of proinflammatory cytokines
Exerts anticonvulsant effect[166]
Agonist effect on GABAA receptors
↓ Glutamate transmission
SchizophreniaQuercetinScavenges free radicals[167]
↑ Levels of antioxidant enzymes
Reduces depressive behaviors[168]
Improves behavioral impairments[169]
Boosts up antipsychotic therapy[170]
DepressionQuercetin↑ Levels of antioxidant enzymes[171,172]
↓ Decrease levels of inflammatory cytokines
Accrues serotonin level
Mitigates depressive behaviors[173]
Modulates levels of BDNF
MyricetinRecovers hopeless behaviors[174,175]
Regulates BDNF levels
Exerts antioxidant effect
KaempferolExert anti-depressive effects[176]
↑ Levels of antioxidant enzymes
Upregulates AKT/β-catenin cascade
ChrysinUpregulates nerve growth factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF)[177]
Normalizes Na+, K+-ATPase activity
Employs anti-depressant effects[178]
Inhibits kynurenine pathway
Elevates the levels of serotonin (5HT)
NaringeninPerforms anti-depressive activity[179]
Restores antioxidant enzymes’ levels
Modulates serotonin levels
Downregulates inflammation mediators
Inhibits acetylcholinesterase activity[180]
Mitigates oxidative damage
Upregulates BDNF, Sonic Hedgehog (Shh) signaling, NKX2.2, and PAX6[181]
Coumaric acidImproves behavioral hopelessness[182]
Lessens inflammation-associated alterations
Enhances neurotrophic activity
Ferulic acidAbrogates depression-like behaviors[183]
Downregulates pro-inflammatory cytokines
Downregulates factors associated with inflammation and apoptosis[184]
Mitigates depression
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Iftikhar, A.; Nausheen, R.; Muzaffar, H.; Naeem, M.A.; Farooq, M.; Khurshid, M.; Almatroudi, A.; Alrumaihi, F.; Allemailem, K.S.; Anwar, H. Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols. Molecules 2022, 27, 3297. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27103297

AMA Style

Iftikhar A, Nausheen R, Muzaffar H, Naeem MA, Farooq M, Khurshid M, Almatroudi A, Alrumaihi F, Allemailem KS, Anwar H. Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols. Molecules. 2022; 27(10):3297. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27103297

Chicago/Turabian Style

Iftikhar, Arslan, Rimsha Nausheen, Humaira Muzaffar, Muhammad Ahsan Naeem, Muhammad Farooq, Mohsin Khurshid, Ahmad Almatroudi, Faris Alrumaihi, Khaled S. Allemailem, and Haseeb Anwar. 2022. "Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols" Molecules 27, no. 10: 3297. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27103297

Article Metrics

Back to TopTop