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Therapeutic Agents for Neurological Disorders 2022
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Therapeutic Agents for Neurological Disorders 2022

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 59495

Special Issue Editor

Dr. Damian Holsinger

E-Mail Website
Guest Editor
Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
Interests: neurodegenerative diseases; Alzheimer’s disease; dementia; cell biology; molecular biology; ageing; therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The World Health Organization defines neurological disorders as disabling conditions that encompass, but are not limited to, cerebrovascular diseases, epilepsy, dementias, including Alzheimer’s, multiple sclerosis, movement disorders resulting from nervous system deficits, brain tumors, neuroinfections and neurological disorders as a result of malnutrition 1. Globally, in 2016, neurological disorders were the leading cause of disability-adjusted life years (DALYs) (276 million (95% UI 247–308)) and the second leading cause of deaths (9.0 million (8.8–9.4)) 2. The absolute number of deaths and DALYs from all neurological disorders combined increased by 39% and 15%, respectively 2. These figures outline an impending epidemic that requires urgent attention. Treatments for neurological disorders are challenging, but numerous advancements have been made in identifying mechanisms and delineating the pathways underlying these diseases. Advances in technologies that garner information from the fields of bioinformatics and next generation and whole genome sequencing have added invaluable support in identifying "culprit" genes and proteins. Using this information, scientists and clinicians have ventured into areas previously deemed "fiction". From brain-controlled, non-invasive muscle stimulators that help paraplegics walk to the editing of the CEP290 gene in individuals with Leber congenital amaurosis 10 (LCA10) and a plethora of therapies in between, biomedicine has made giant leaps in just over two decades. In this Special Issue, we aim to draw together research from experts in the field that highlight therapeutic agents and strategies, as well as identify future directions that will lead to discoveries and therapies for neurological disorders. 

1 http://www.who.int/features/qa/55/en

2 GBD 2016 Neurology Collaborators (2019). Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18: 459–80.

Dr. Damian Holsinger
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegeneration
  • brain injury
  • spinal cord injury
  • neurodevelopmental disorders
  • nerve repair
  • brain tumors
  • neuromodulation
  • neuroinflammation

Published Papers (18 papers)

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21 pages, 46533 KiB  
Article
Fiber and Electrical Field Alignment Increases BDNF Expression in SH-SY5Y Cells following Electrical Stimulation
by Quy-Susan Huynh and R. M. Damian Holsinger
Pharmaceuticals 2023, 16(2), 138; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16020138 - 17 Jan 2023
Cited by 1 | Viewed by 1296
Abstract
The limited expression of neurotrophic factors that can be included in neural tissue engineering scaffolds is insufficient for sustained neural regeneration. A localized and sustained method of introducing neurotrophic factors is required. We describe our attempt at inducing neuroblastoma cells to express trophic [...] Read more.
The limited expression of neurotrophic factors that can be included in neural tissue engineering scaffolds is insufficient for sustained neural regeneration. A localized and sustained method of introducing neurotrophic factors is required. We describe our attempt at inducing neuroblastoma cells to express trophic factors following electrical stimulation. Human SH-SY5Y neuroblastoma cells, cultured on polycaprolactone electrospun nanofibers, were electrically stimulated using a 100 mV/mm electric field. Nuclear morphology and brain-derived neurotrophic factor (BDNF) expression were analyzed. Cells were classified based on the type of fiber orientation and the alignment of these fibers in relation to the electric field. Nuclear deformation was mainly influenced by fiber orientation rather than the electrical field. Similarly, fiber orientation also induced BDNF expression. Although electrical field alone had no significant effect on BDNF expression, combining fiber orientation with electrical field resulted in BDNF expression in cells that grew on electrospun fibers that were aligned perpendicular to the electrical field. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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9 pages, 990 KiB  
Article
Antiepileptic Effect of Neuroaid® on Strychnine-Induced Convulsions in Mice
by Ahmed Salim Mahmood, Afaq M. Ammoo, Mayssam Hussein Mohammed Ali, Tiba M. Hameed, Hany A. Al-Hussaniy, Abdulla Amer Abbas Aljumaili, Mohammed Hussein Alaa Al-Fallooji and Ali Hakim Kadhim
Pharmaceuticals 2022, 15(12), 1468; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121468 - 26 Nov 2022
Cited by 17 | Viewed by 1981
Abstract
NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in [...] Read more.
NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in the prevention of epilepsy (EP). Forty healthy adult male mice were used and divided into four groups (10 mice/group): normal control group; positive control group; NeuroAid-treated group (10 mg/kg); topiramate-treated group (10 mg/kg). The treatment continued for 7 days, and on the last day, EP was induced using strychnine at a dose of 2 mg/kg via intraperitoneal (ip) administration. Seizure severity, latency to the seizure onset, the number of seizures, and the duration of each seizure episode were observed for one hour. The death and protection rates over the next twenty-four hours were recorded. Brain specimens from surviving animals were extracted and examined pathologically for quantification of glutamate receptor (GluR) gene expression in the isolated hippocampus employing real-time PCR analysis. Treatment with NeuroAid resulted in a significant reduction in seizure severity, prolonged the onset of seizures, decreased the number and duration of episodes, reduced brain insult, and decreased mortality rate. Reductions in the gene expression of GluRs in the hippocampus with minor histopathological changes were observed in the NeruoAid- and topiramate-treated groups. It is concluded that NeuroAid has a potential antiepileptic effect (EP) with the ability to prevent convulsion through its effect on the glutamate receptor. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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12 pages, 1145 KiB  
Article
Relationship between Patient Preferences, Attitudes to Treatment, Adherence, and Quality of Life in New Users of Teriflunomide
by Daniela Štrosová, Jan Tužil, Barbora Velacková Turková, Barbora Filková Pilnáčková, Lada Lžičařová de Souza, Helena Doležalová, Michaela Rašková, Michal Dufek and Tomáš Doležal
Pharmaceuticals 2022, 15(10), 1248; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101248 - 11 Oct 2022
Cited by 1 | Viewed by 2210
Abstract
Background: A poor patient adherence often limits the real-world effectiveness of an oral disease-modifying therapy (DMT) for multiple sclerosis (MS). In the present study, we aimed to map patient preferences, attitudes toward treatment, and quality of life to identify the predictors of non-adherence [...] Read more.
Background: A poor patient adherence often limits the real-world effectiveness of an oral disease-modifying therapy (DMT) for multiple sclerosis (MS). In the present study, we aimed to map patient preferences, attitudes toward treatment, and quality of life to identify the predictors of non-adherence to teriflunomide. Methods: This was a single-arm, non-interventional, multicenter study (Czech Act 378/2007 Coll.) consisting of three visits: the first at treatment initiation (teriflunomide 14 mg), and then after 3 and 9 months of therapy. We enrolled both DMT-naïve and patients who had undergone a DMT diagnosed with a clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS). The functional status and MS activity were estimated using the Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR); the quality of life via the Multiple Sclerosis Impact Scale (MSIS-29); the medication adherence with the Morisky Medication Adherence Scale (MMAS-8); the confidence in the ability to take medications by the Self-Efficacy for Appropriate Medication Score (SEAMS); and the attitude to the therapy via the Beliefs about Medicines Questionnaire (BMQ). After nine months of therapy, we predicted the adherence to teriflunomide (MMAS-8) by fitting a multivariate ordinal logistic model with EDSS changes, gender, previous DMT, MSIS-29, BMQ, and SEAMS as the explanatory variables. Results: Between 2018 and 2019, 114 patients were enrolled at 10 sites in the Czech Republic. The mean age was 41.2 years, 64.8% were diagnosed with a CIS, 52.4% were DMT-naïve, and 98.1% of patients preferred an oral administration at the baseline. The mean EDSS baseline was 1.97 and remained constant during the 9 months of therapy. The ARR baseline was 0.72 and dropped to 0.19 and 0.15 after 3 and 9 months, respectively. Despite a more than 4-fold higher ARR baseline, the treatment-naïve patients achieved an ARR at 9 months comparable with those previously treated. There were ten non-serious adverse reactions. After nine months of teriflunomide therapy, 63.3%, 21.2%, and 15.4% of patients had a high, medium, and low adherence, respectively, as per the MMAS-8; 100% of patients preferred an oral administration. The SEAMS score (odds ratio (OR) = 0.91; p = 0.013) and previous DMT (OR = 4.28; p = 0.005) were the only significant predictors of non-adherence. The disability, the quality of life, and beliefs about medicines had no measurable effect on adherence. Conclusion: After nine months of teriflunomide therapy, both the disability and quality of life remained stable; the relapse rate significantly decreased, 63.3% of patients had a high adherence, and 100% of patients preferred an oral administration. A low adherence was associated with previous DMT experiences and a low self-efficacy for the appropriate medication (i.e., the confidence in one’s ability to take medication correctly). Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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12 pages, 4047 KiB  
Article
Pioglitazone Ameliorates Hippocampal Neurodegeneration, Disturbances in Glucose Metabolism and AKT/mTOR Signaling Pathways in Pentyelenetetrazole-Kindled Mice
by Nada El-Megiri, Yasser M. Mostafa, Amal Ahmed, Eman T. Mehanna, Mona F. El-Azab, Fatma Alshehri, Hadil Alahdal and Norhan M. El-Sayed
Pharmaceuticals 2022, 15(9), 1113; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091113 - 06 Sep 2022
Cited by 1 | Viewed by 1694
Abstract
Disturbance of glucose metabolism, nerve growth factor (NGF) and m-TOR signaling have been associated with the pathophysiology of epilepsy. Pioglitazone (PGZ) is an anti-diabetic drug that shows a protective effect in neurodegenerative diseases including epilepsy; however, its exact mechanism is not fully elucidated. [...] Read more.
Disturbance of glucose metabolism, nerve growth factor (NGF) and m-TOR signaling have been associated with the pathophysiology of epilepsy. Pioglitazone (PGZ) is an anti-diabetic drug that shows a protective effect in neurodegenerative diseases including epilepsy; however, its exact mechanism is not fully elucidated. The present study aimed to investigate the potential neuroprotective effect of PGZ in pentylenetetrazole (PTZ) kindled seizure in mice. Swiss male albino mice were randomly distributed into four groups, each having six mice. Group 1 was considered the control. Epilepsy was induced by PTZ (35 mg/kg i.p.) thrice a week for a total of 15 injections in all other groups. Group 2 was considered the untreated PTZ group while Group 3 and Group 4 were treated by PGZ prior to PTZ injection at two dose levels (5 and 10 mg/kg p.o., respectively). Seizure activity was evaluated after each PTZ injection according to the Fischer and Kittner scoring system. At the end of the experiment, animals were sacrificed under deep anesthesia and the hippocampus was isolated for analysis of glucose transporters by RT-PCR, nerve growth factor (NGF) by ELISA and mTOR by western blotting, in addition to histopathological investigation. The PTZ-treated group showed a significant rise in seizure score, NGF and m-TOR hyperactivation, along with histological abnormalities compared to the control group. Treatment with PGZ demonstrated a significant decrease in NGF, seizure score, m-TOR, GLUT-1 and GLUT-3 in comparison to the PTZ group. In addition, improvement of histological features was observed in both PGZ treated groups. These findings suggest that PGZ provides its neuroprotective effect through modulating m-TOR signaling, glucose metabolism and NGF levels. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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8 pages, 597 KiB  
Article
Alzheimer’s Disease Severity Is Associated with an Imbalance in Serum Levels of Enzymes Regulating Plasmin Synthesis
by Francesco Angelucci, Katerina Veverova, Alžbeta Katonová, Lydia Piendel, Martin Vyhnalek and Jakub Hort
Pharmaceuticals 2022, 15(9), 1074; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091074 - 29 Aug 2022
Cited by 6 | Viewed by 1610
Abstract
Alzheimer’s disease (AD) is a central nervous system (CNS) disease characterized by loss of memory, cognitive functions, and neurodegeneration. Plasmin is an enzyme degrading many plasma proteins. In the CNS, plasmin may reduce the accumulation of beta amyloid (Aβ) and have other actions [...] Read more.
Alzheimer’s disease (AD) is a central nervous system (CNS) disease characterized by loss of memory, cognitive functions, and neurodegeneration. Plasmin is an enzyme degrading many plasma proteins. In the CNS, plasmin may reduce the accumulation of beta amyloid (Aβ) and have other actions relevant to AD pathophysiology. Brain plasmin synthesis is regulated by two enzymes: one activating, the tissue plasminogen activator (tPA), and the other inhibiting, the plasminogen activator inhibitor-1 (PAI-1). We investigated the levels of tPA and PAI-1 in serum from 40 AD and 40 amnestic mild cognitively impaired (aMCI) patients compared to 10 cognitively healthy controls. Moreover, we also examined the PAI-1/tPA ratio in these patient groups. Venous blood was collected and the PAI-1 and tPA serum concentrations were quantified using sandwich ELISAs. The results showed that PAI-1 levels increased in AD and aMCI patients. This increase negatively correlated with cognitive performance measured using the Mini-Mental Status Exam (MMSE). Similarly, the ratio between tPA and PAI-1 gradually increases in aMCI and AD patients. This study demonstrates that AD and aMCI patients have altered PAI-1 serum levels and PAI-1/tPA ratio. Since these enzymes are CNS regulators of plasmin, PAI-1 serum levels could be a marker reflecting cognitive decline in AD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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12 pages, 915 KiB  
Article
Glucoraphanin Triggers Rapid Antidepressant Responses in a Rat Model of Beta Amyloid-Induced Depressive-like Behaviour
by Paolo Tucci, Maria Bove, Vladyslav Sikora, Stefania Dimonte, Maria Grazia Morgese, Stefania Schiavone, Lorenzo Di Cesare Mannelli, Carla Ghelardini and Luigia Trabace
Pharmaceuticals 2022, 15(9), 1054; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091054 - 26 Aug 2022
Cited by 4 | Viewed by 1381
Abstract
Glucoraphanin (GRA) is a natural compound that has shown beneficial effects in chronic diseases and in central nervous system disorders. Moreover, GRA displayed antidepressant activity in preclinical models. We have previously demonstrated that a single intracerebroventricular administration of soluble amyloid-beta 1-42 (sAβ 1-42) [...] Read more.
Glucoraphanin (GRA) is a natural compound that has shown beneficial effects in chronic diseases and in central nervous system disorders. Moreover, GRA displayed antidepressant activity in preclinical models. We have previously demonstrated that a single intracerebroventricular administration of soluble amyloid-beta 1-42 (sAβ 1-42) in rat evokes a depressive-like phenotype by increasing immobility frequency in the forced swimming test (FST). The aim of this work was to investigate the effect of GRA in naïve and in sAβ-1-42-treated rats by using the FST. Behavioural analyses were accompanied by neurochemical and biochemical measurements in the prefrontal cortex (PFC), such as serotonin (5-HT), noradrenaline (NA), kynurenine (KYN), tryptophan (TRP), reactive oxygen species (ROS) and the transcription nuclear factor kappa B (NF-kB) levels. We reported that GRA administration in naïve rats at the dose of 50 mg/kg reduced the immobility frequency in the FST and increased 5-HT and NA levels in the PFC compared to controls. At the same dose, GRA reverted depressive-like effects of sAβ 1-42 administration, restored the 5-HT levels and reduced NF-kB, KYN and ROS levels in PFC. In conclusion, GRA rapidly reverting depressive-like behaviour, together with biochemical and neurochemical alterations, might represent a safe and natural candidate for the treatment of depression. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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19 pages, 2025 KiB  
Article
Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
by Nermin Eissa, Karthikkumar Venkatachalam, Petrilla Jayaprakash, Priya Yuvaraju, Markus Falkenstein, Holger Stark and Bassem Sadek
Pharmaceuticals 2022, 15(8), 929; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080929 - 27 Jul 2022
Viewed by 1942
Abstract
Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic [...] Read more.
Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H3R/D2R/D3R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H3R/D2R/D3R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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13 pages, 1397 KiB  
Article
miR-182-5p Regulates Nogo-A Expression and Promotes Neurite Outgrowth of Hippocampal Neurons In Vitro
by Altea Soto, Manuel Nieto-Díaz, David Reigada, María Asunción Barreda-Manso, Teresa Muñoz-Galdeano and Rodrigo M. Maza
Pharmaceuticals 2022, 15(5), 529; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050529 - 25 Apr 2022
Cited by 4 | Viewed by 2449
Abstract
Nogo-A protein is a key myelin-associated inhibitor of axonal growth, regeneration, and plasticity in the central nervous system (CNS). Regulation of the Nogo-A/NgR1 pathway facilitates functional recovery and neural repair after spinal cord trauma and ischemic stroke. MicroRNAs are described as effective tools [...] Read more.
Nogo-A protein is a key myelin-associated inhibitor of axonal growth, regeneration, and plasticity in the central nervous system (CNS). Regulation of the Nogo-A/NgR1 pathway facilitates functional recovery and neural repair after spinal cord trauma and ischemic stroke. MicroRNAs are described as effective tools for the regulation of important processes in the CNS, such as neuronal differentiation, neuritogenesis, and plasticity. Our results show that miR-182-5p mimic specifically downregulates the expression of the luciferase reporter gene fused to the mouse Nogo-A 3′UTR, and Nogo-A protein expression in Neuro-2a and C6 cells. Finally, we observed that when rat primary hippocampal neurons are co-cultured with C6 cells transfected with miR-182-5p mimic, there is a promotion of the outgrowth of neuronal neurites in length. From all these data, we suggest that miR-182-5p may be a potential therapeutic tool for the promotion of axonal regeneration in different diseases of the CNS. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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28 pages, 6360 KiB  
Article
Transcriptomic Analysis of Fumarate Compounds Identifies Unique Effects of Isosorbide Di-(Methyl Fumarate) on NRF2, NF-kappaB and IRF1 Pathway Genes
by William R. Swindell, Krzysztof Bojanowski and Ratan K. Chaudhuri
Pharmaceuticals 2022, 15(4), 461; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040461 - 11 Apr 2022
Cited by 4 | Viewed by 2192
Abstract
Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the effects of fumarates on gene expression in [...] Read more.
Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-κB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-κB inhibition, and we confirmed IDMF-mediated NF-κB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition sequences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates, such as DRF and IDMF, have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-κB and IRF1 contributing to mitigation of inflammation and pyroptosis. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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11 pages, 744 KiB  
Article
Association between Proton Pump Inhibitor Use and Parkinson’s Disease in a Korean Population
by Ji-Hee Kim, Jae-Keun Oh, Yoo-Hwan Kim, Mi-Jung Kwon, Joo-Hee Kim and Hyo-Geun Choi
Pharmaceuticals 2022, 15(3), 327; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030327 - 09 Mar 2022
Cited by 5 | Viewed by 2644
Abstract
Few studies have shown an increased risk of Parkinson’s disease (PD) with the use of proton pump inhibitors (PPIs), and the pathophysiological mechanism for this association has not been unveiled. This study examined the relationship between PPI use and PD in a Korean [...] Read more.
Few studies have shown an increased risk of Parkinson’s disease (PD) with the use of proton pump inhibitors (PPIs), and the pathophysiological mechanism for this association has not been unveiled. This study examined the relationship between PPI use and PD in a Korean population. We investigated 3026 PD patients and 12,104 controls who were matched by age, sex, income, and region of residence at a ratio of 1:4 in the Korean National Health Insurance Service, National Sample Cohort between 2002 and 2015. We estimated the associations between current and past use of PPIs and PD using odds ratios (ORs) and 95% confidence intervals (CIs) in a conditional/unconditional logistic regression after adjusting for probable confounders. Compared with PPI nonusers, both current users and past users had significantly greater odds of having PD, with ORs of 1.63 (95% CI = 1.44–1.84) and 1.12 (95% CI = 1.01–1.25), respectively. A significant association with PD was observed in individuals who used PPIs for 30–90 days and ≥90 days (OR = 1.26 and 1.64, 95% CI = 1.12–1.43 and 1.43–1.89) but not among those who used PPIs for <30 days. Both current and past use of PPIs associated with a higher probability of PD in the Korean population. Our study provides evidence regarding the association between PPI exposure and PD, but further investigation and possible explanations are warranted. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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17 pages, 2615 KiB  
Article
How Molecular Topology Can Help in Amyotrophic Lateral Sclerosis (ALS) Drug Development: A Revolutionary Paradigm for a Merciless Disease
by Maria Galvez-Llompart, Riccardo Zanni, Ramon Garcia-Domenech and Jorge Galvez
Pharmaceuticals 2022, 15(1), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010094 - 14 Jan 2022
Cited by 2 | Viewed by 2811
Abstract
Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well [...] Read more.
Even if amyotrophic lateral sclerosis is still considered an orphan disease to date, its prevalence among the population is growing fast. Despite the efforts made by researchers and pharmaceutical companies, the cryptic information related to the biological and physiological onset mechanisms, as well as the complexity in identifying specific pharmacological targets, make it almost impossible to find effective treatments. Furthermore, because of complex ethical and economic aspects, it is usually hard to find all the necessary resources when searching for drugs for new orphan diseases. In this context, computational methods, based either on receptors or ligands, share the capability to improve the success rate when searching and selecting potential candidates for further experimentation and, consequently, reduce the number of resources and time taken when delivering a new drug to the market. In the present work, a computational strategy based on Molecular Topology, a mathematical paradigm capable of relating the chemical structure of a molecule to a specific biological or pharmacological property by means of numbers, is presented. The result was the creation of a reliable and accessible tool to help during the early in silico stages in the identification and repositioning of potential hits for ALS treatment, which can also apply to other orphan diseases. Considering that further computational and experimental results will be required for the final identification of viable hits, three linear discriminant equations combined with molecular docking simulations on specific proteins involved in ALS are reported, along with virtual screening of the Drugbank database as a practical example. In this particular case, as reported, a clinical trial has been already started for one of the drugs proposed in the present study. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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19 pages, 10692 KiB  
Article
Combined Treatment with Acalabrutinib and Rapamycin Inhibits Glioma Stem Cells and Promotes Vascular Normalization by Downregulating BTK/mTOR/VEGF Signaling
by Yu-Kai Su, Oluwaseun Adebayo Bamodu, I-Chang Su, Narpati Wesa Pikatan, Iat-Hang Fong, Wei-Hwa Lee, Chi-Tai Yeh, Hsiao-Yean Chiu and Chien-Min Lin
Pharmaceuticals 2021, 14(9), 876; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090876 - 29 Aug 2021
Cited by 10 | Viewed by 2778
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular [...] Read more.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median duration of survival of approximately 14 months after diagnosis. High resistance to chemotherapy remains a major problem. Previously, BTK has been shown to be involved in the intracellular signal transduction including Akt/mTOR signaling and be critical for tumorigenesis. Thus, we aim to evaluate the effect of BTK and mTOR inhibition in GBM. We evaluated the viability of GBM cell lines after treatment with acalabrutinib and/or rapamycin through a SRB staining assay. We then evaluated the effect of both drugs on GBM stem cell-like phenotypes through various in vitro assay. Furthermore, we incubated HUVEC cells with tumorsphere conditioned media and observed their angiogenesis potential, with or without treatment. Finally, we conducted an in vivo study to confirm our in vitro findings and analyzed the effect of this combination on xenograft mice models. Drug combination assay demonstrated a synergistic relationship between acalabrutinib and rapamycin. CSCs phenotypes, including tumorsphere and colony formation with the associated expression of markers of pluripotency are inhibited by either acalabrutinib or rapamycin singly and these effects are enhanced upon combining acalabrutinib and rapamycin. We showed that the angiogenesis capabilities of HUVEC cells are significantly reduced after treatment with acalabrutinib and/or rapamycin. Xenograft tumors treated with both drugs showed significant volume reduction with minimal toxicity. Samples taken from the combined treatment group demonstrated an increased Desmin/CD31 and col IV/vessel ratio, suggesting an increased rate of vascular normalization. Our results demonstrate that BTK-mTOR inhibition disrupts the population of GBM-CSCs and contributes to normalizing GBM vascularization and thus, may serve as a basis for developing therapeutic strategies for chemoresistant/radioresistant GBM. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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Review

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30 pages, 1289 KiB  
Review
FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders
by Austin Lui, Jordan Vanleuven, David Perekopskiy, Dewey Liu, Desiree Xu, Omar Alzayat, Taiseer Elgokhy, Timothy Do, Meghan Gann, Ryan Martin and Da-Zhi Liu
Pharmaceuticals 2022, 15(12), 1546; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121546 - 13 Dec 2022
Cited by 5 | Viewed by 7485
Abstract
Cancers and neurological disorders are two major types of diseases. We previously developed a new concept termed “Aberrant Cell Cycle Diseases” (ACCD), revealing that these two diseases share a common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested [...] Read more.
Cancers and neurological disorders are two major types of diseases. We previously developed a new concept termed “Aberrant Cell Cycle Diseases” (ACCD), revealing that these two diseases share a common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncogene activation and tumor suppressor inactivation, which are hallmarks of both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase inhibition, tumor suppressor elevation) can be leveraged for neurological treatments. The United States Food and Drug Administration (US FDA) has so far approved 74 kinase inhibitors, with numerous other kinase inhibitors in clinical trials, mostly for the treatment of cancers. In contrast, there are dire unmet needs of FDA-approved drugs for neurological treatments, such as Alzheimer’s disease (AD), intracerebral hemorrhage (ICH), ischemic stroke (IS), traumatic brain injury (TBI), and others. In this review, we list these 74 FDA-approved kinase-targeted drugs and identify those that have been reported in preclinical and/or clinical trials for neurological disorders, with a purpose of discussing the feasibility and applicability of leveraging these cancer drugs (FDA-approved kinase inhibitors) for neurological treatments. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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16 pages, 862 KiB  
Review
Nutraceutical Interventions for Post-Traumatic Stress Disorder in Animal Models: A Focus on the Hypothalamic–Pituitary–Adrenal Axis
by Mudan Cai, Hee Ra Park and Eun Jin Yang
Pharmaceuticals 2022, 15(7), 898; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070898 - 20 Jul 2022
Cited by 4 | Viewed by 4440
Abstract
Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the [...] Read more.
Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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25 pages, 36165 KiB  
Review
New Paradigms of Old Psychedelics in Schizophrenia
by Danish Mahmood, Sattam K. Alenezi, Md. Jamir Anwar, Faizul Azam, Kamal A. Qureshi and Mariusz Jaremko
Pharmaceuticals 2022, 15(5), 640; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050640 - 23 May 2022
Cited by 5 | Viewed by 8005
Abstract
Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned [...] Read more.
Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin–glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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23 pages, 1254 KiB  
Review
Role of Brain Modulators in Neurodevelopment: Focus on Autism Spectrum Disorder and Associated Comorbidities
by Ali K. Saad, Amal Akour, Abdulla Mahboob, Salahdein AbuRuz and Bassem Sadek
Pharmaceuticals 2022, 15(5), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050612 - 16 May 2022
Cited by 9 | Viewed by 3360
Abstract
Autism spectrum disorder (ASD) and associated neurodevelopmental disorders share similar pathogenesis and clinical features. Pathophysiological changes in these diseases are rooted in early neuronal stem cells in the uterus. Several genetic and environmental factors potentially perturb neurogenesis and synaptogenesis processes causing incomplete or [...] Read more.
Autism spectrum disorder (ASD) and associated neurodevelopmental disorders share similar pathogenesis and clinical features. Pathophysiological changes in these diseases are rooted in early neuronal stem cells in the uterus. Several genetic and environmental factors potentially perturb neurogenesis and synaptogenesis processes causing incomplete or altered maturation of the brain that precedes the symptomology later in life. In this review, the impact of several endogenous neuromodulators and pharmacological agents on the foetus during pregnancy, manifested on numerous aspects of neurodevelopment is discussed. Within this context, some possible insults that may alter these modulators and therefore alter their role in neurodevelopment are high-lighted. Sometimes, a particular insult could influence several neuromodulator systems as is supported by recent research in the field of ASD and associated disorders. Dopaminergic hy-pothesis prevailed on the table for discussion of the pathogenesis of schizophrenia (SCH), atten-tion-deficit hyperactivity disorder (ADHD) and ASD for a long time. However, recent cumulative evidence suggests otherwise. Indeed, the neuromodulators that are dysregulated in ASD and comorbid disorders are as diverse as the causes and symptoms of this disease. Additionally, these neuromodulators have roles in brain development, further complicating their involvement in comorbidity. This review will survey the current understanding of the neuromodulating systems to serve the pharmacological field during pregnancy and to minimize drug-related insults in pa-tients with ASD and associated comorbidity disorders, e.g., SCH or ADHD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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29 pages, 1755 KiB  
Review
Current and Emerging Pharmacotherapeutic Interventions for the Treatment of Peripheral Nerve Disorders
by Jeremy Chung Bo Chiang, Ria Arnold, Roshan Dhanapalaratnam, Maria Markoulli and Arun V. Krishnan
Pharmaceuticals 2022, 15(5), 607; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050607 - 15 May 2022
Cited by 3 | Viewed by 3933
Abstract
Peripheral nerve disorders are caused by a range of different aetiologies. The range of causes include metabolic conditions such as diabetes, obesity and chronic kidney disease. Diabetic neuropathy may be associated with severe weakness and the loss of sensation, leading to gangrene and [...] Read more.
Peripheral nerve disorders are caused by a range of different aetiologies. The range of causes include metabolic conditions such as diabetes, obesity and chronic kidney disease. Diabetic neuropathy may be associated with severe weakness and the loss of sensation, leading to gangrene and amputation in advanced cases. Recent studies have indicated a high prevalence of neuropathy in patients with chronic kidney disease, also known as uraemic neuropathy. Immune-mediated neuropathies including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy may cause significant physical disability. As survival rates continue to improve in cancer, the prevalence of treatment complications, such as chemotherapy-induced peripheral neuropathy, has also increased in treated patients and survivors. Notably, peripheral neuropathy associated with these conditions may be chronic and long-lasting, drastically affecting the quality of life of affected individuals, and leading to a large socioeconomic burden. This review article explores some of the major emerging clinical and experimental therapeutic agents that have been investigated for the treatment of peripheral neuropathy due to metabolic, toxic and immune aetiologies. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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Other

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19 pages, 2004 KiB  
Systematic Review
Comparative Effectiveness of Injection Therapies for Hemiplegic Shoulder Pain in Stroke: A Systematic Review and Network Meta-Analysis
by Yi-Hsiang Chiu, Ke-Vin Chang, Wei-Ting Wu, Po-Cheng Hsu and Levent Özçakar
Pharmaceuticals 2021, 14(8), 788; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080788 - 10 Aug 2021
Cited by 13 | Viewed by 4827
Abstract
Hemiplegic shoulder pain (HSP) hampers post-stroke functional recovery and is not well managed with conservative treatments. This systematic review aimed to examine the various injection therapies for HSP and investigate their effectiveness at different time points. The protocol of this meta-analysis was registered [...] Read more.
Hemiplegic shoulder pain (HSP) hampers post-stroke functional recovery and is not well managed with conservative treatments. This systematic review aimed to examine the various injection therapies for HSP and investigate their effectiveness at different time points. The protocol of this meta-analysis was registered on INPLASY with a registration number of INPLASY202180010. PubMed, EMBASE, and Scopus were searched from their inception to 4 August 2021 for the clinical studies investigating comparative effectiveness of different injection regimens for treating hemiplegic shoulder pain in patients with stroke. The primary outcome was the weighted mean difference (WMD) on the visual analog scale (VAS) of pain reduction in the fourth-week and between the fourth and twenty-fourth weeks. Ranking probabilities of the WMD for each treatment were obtained using simulations. Seventeen studies with 595 participants were included. The network meta-analysis showed that at the fourth-week, intra-muscular botulinum toxin (BoNT) injections and suprascapular nerve blocks (SSNB) were superior to a placebo, with WMDs of 1.55 (95% CI, 0.09 to 3.01) and 1.44 (95% CI, 0.07 to 2.80), respectively. SSNB possessed the highest probability (53.3%) and appeared to be the best treatment in the fourth-week, followed by intra-muscular BoNT injections (42.6%). Intramuscular BoNT injections were better than the placebo, with a WMD of 1.57 (95% CI, 0.30 to 2.84) between the 4th and 24th weeks. Intramuscular BoNT injections had the highest probability (79.8%) as the best treatment between the 4th and 24th weeks. SSNB was likely to rank first in relieving HSP at the fourth post-treatment week, whereas intra-muscular BoNT injections had the highest probability to achieve the best treatment effectiveness in the post-injection period between the fourth and twenty-fourth weeks. However, as some of the included studies used a non-randomized controlled design, more randomized controlled trials are needed in the future to validate and better understand the short- and long-term efficacy of different injection therapies for management of HSP. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)
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