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Neuroinflammation Toxicity and Neuroprotection

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 22293

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Special Issue Editor

Dr. Ming-Chang Chiang

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Guest Editor

Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei 242304, Taiwan
Interests: neuroinflammation toxicity and neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroinflammation is the beginning of all brain lesions. Neuroinflammation is a real risk factor for the development and progression of the brain and neurodegenerative diseases. In addition, neuroinflammation has a vital role in developing pathology resulting from the interaction of neuronal and glial cells. Thus, an extensive literature dataset suggests that inflammation is the cause of neurotoxicity. Many cellular functions are altered during inflammation, such as mitochondrial dysregulation, oxidative stress, ER stress, cell signaling, and other fundamental mechanisms. Therefore, the authors are invited to publish in vitro and in vivo papers exploring the pathophysiology of neuroinflammatory toxicity in neurodegenerative diseases, stroke, brain tumors, and the role of PM2.5 pollution while discussing neuroprotective effects.

This Special Issue aims to collect the pathological mechanisms of neuroinflammation-induced toxicity in the fields of neurodegenerative diseases, stroke, brain tumors, and PM2.5 air pollution. It will include original research articles or review papers on the molecular mechanisms of cytotoxicity induced by different injuries. Additional potential neuroprotective topics include drugs, natural anti-inflammatory agents, and nanomedicines that may play a key role in developing new strategies for therapeutic drugs in the development of neuroinflammatory symptoms.

Dr. Ming-Chang Chiang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

neuroinflammation neurotoxicity
neurotoxicity
neuroprotection
neurodegenerative diseases
stroke
brain tumors
anti-inflammatory agents

Published Papers (9 papers)

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Research

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13 pages, 4116 KiB

Open AccessArticle

Exposure to Benzo[a]pyrene Decreases Noradrenergic and Serotonergic Axons in Hippocampus of Mouse Brain

by Walaa Slouma Hamouda Abd El Naby, Cai Zong, Alzahraa Fergany, Frederick Adams Ekuban, Saleh Ahmed, Yousra Reda, Harue Sato, Sahoko Ichihara, Natsuko Kubota, Shinya Yanagita and Gaku Ichihara

Int. J. Mol. Sci. 2023, 24(12), 9895; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129895 - 08 Jun 2023

Cited by 1 | Viewed by 1681

Abstract

Epidemiological studies showed the association between air pollution and dementia. A soluble fraction of particulate matters including polycyclic aromatic hydrocarbons (PAHs) is suspected to be involved with the adverse effects of air pollution on the central nervous system of humans. It is also reported that exposure to benzopyrene (B[a]P), which is one of the PAHs, caused deterioration of neurobehavioral performance in workers. The present study investigated the effect of B[a]P on noradrenergic and serotonergic axons in mouse brains. In total, 48 wild-type male mice (10 weeks of age) were allocated into 4 groups and exposed to B[a]P at 0, 2.88, 8.67 or 26.00 µg/mice, which is approximately equivalent to 0.12, 0.37 and 1.12 mg/kg bw, respectively, by pharyngeal aspiration once/week for 4 weeks. The density of noradrenergic and serotonergic axons was evaluated by immunohistochemistry in the hippocampal CA1 and CA3 areas. Exposure to B[a]P at 2.88 µg/mice or more decreased the density of noradrenergic or serotonergic axons in the CA1 area and the density of noradrenergic axons in the CA3 area in the hippocampus of mice. Furthermore, exposure to B[a]P dose-dependently upregulated Tnfα at 8.67 µg/mice or more, as well as upregulating Il-1β at 26 µg/mice, Il-18 at 2.88 and 26 µg/mice and Nlrp3 at 2.88 µg/mice. The results demonstrate that exposure to B[a]P induces degeneration of noradrenergic or serotonergic axons and suggest the involvement of proinflammatory or inflammation-related genes with B[a]P-induced neurodegeneration. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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15 pages, 3094 KiB

Open AccessArticle

Acetylsalicylic Acid Supplementation Affects the Neurochemical Phenotyping of Porcine Duodenal Neurons

by Marta Brzozowska and Jarosław Całka

Int. J. Mol. Sci. 2023, 24(12), 9871; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129871 - 07 Jun 2023

Cited by 1 | Viewed by 1132

Abstract

Aspirin (ASA) is a popular nonsteroidal anti-inflammatory drug (NSAID), which exerts its therapeutic properties through the inhibition of cyclooxygenase (COX) isoform 2 (COX-2), while the inhibition of COX-1 by ASA results in the formation of gastrointestinal side effects. Due to the fact that the enteric nervous system (ENS) is involved in the regulation of digestive functions both in physiological and pathological states, the aim of this study was to determine the influence of ASA on the neurochemical profile of enteric neurons in the porcine duodenum. Our research, conducted using the double immunofluorescence technique, proved an increase in the expression of selected enteric neurotransmitters in the duodenum as a result of ASA treatment. The mechanisms of the visualized changes are not entirely clear but are probably related to the enteric adaptation to inflammatory conditions resulting from aspirin supplementation. A detailed understanding of the role of the ENS in the development of drug-induced inflammation will contribute to the establishment of new strategies for the treatment of NSAID-induced lesions. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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12 pages, 989 KiB

Open AccessArticle

ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia

by Jiebo Zhu, Min Joung Lee, Jong Hun An, Eungseok Oh, Woosuk Chung and Jun Young Heo

Int. J. Mol. Sci. 2023, 24(4), 3322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043322 - 07 Feb 2023

Cited by 4 | Viewed by 1937

Abstract

The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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22 pages, 8713 KiB

Open AccessArticle

APP Knock-In Mice Produce E22P-Aβ Exhibiting an Alzheimer’s Disease-like Phenotype with Dysregulation of Hypoxia-Inducible Factor Expression

by Takahito Maki, Masahito Sawahata, Ichiro Akutsu, Shohei Amaike, Genki Hiramatsu, Daisuke Uta, Naotaka Izuo, Takahiko Shimizu, Kazuhiro Irie and Toshiaki Kume

Int. J. Mol. Sci. 2022, 23(21), 13259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113259 - 31 Oct 2022

Cited by 4 | Viewed by 2069

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that requires further pathological elucidation to establish effective treatment strategies. We previously showed that amyloid β (Aβ) toxic conformer with a turn at positions 22–23 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model App^{NL-P-F/NL-P-F} (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aβ, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of Aβ plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1α was increased, and gene expression of HIF-3α was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic Aβ on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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20 pages, 4316 KiB

Open AccessArticle

Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

by Ming-Chang Chiang, Christopher J. B. Nicol, Shy-Shyong Lo, Shiang-Wei Hung, Chieh-Ju Wang and Chien-Hung Lin

Int. J. Mol. Sci. 2022, 23(19), 11678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911678 - 02 Oct 2022

Cited by 7 | Viewed by 2266

Abstract

Oxygen glucose deprivation (OGD) can produce hypoxia-induced neurotoxicity and is a mature in vitro model of hypoxic cell damage. Activated AMP-activated protein kinase (AMPK) regulates a downstream pathway that substantially increases bioenergy production, which may be a key player in physiological energy and has also been shown to play a role in regulating neuroprotective processes. Resveratrol is an effective activator of AMPK, indicating that it may have therapeutic potential as a neuroprotective agent. However, the mechanism by which resveratrol achieves these beneficial effects in SH-SY5Y cells exposed to OGD-induced inflammation and oxidative stress in a 3D gelatin scaffold remains unclear. Therefore, in the present study, we investigated the effect of resveratrol in 3D gelatin scaffold cells to understand its neuroprotective effects on NF-κB signaling, NLRP3 inflammasome, and oxidative stress under OGD conditions. Here, we show that resveratrol improves the expression levels of cell viability, inflammatory cytokines (TNF-α, IL-1β, and IL-18), NF-κB signaling, and NLRP3 inflammasome, that OGD increases. In addition, resveratrol rescued oxidative stress, nuclear factor-erythroid 2 related factor 2 (Nrf2), and Nrf2 downstream antioxidant target genes (e.g., SOD, Gpx GSH, catalase, and HO-1). Treatment with resveratrol can significantly normalize OGD-induced changes in SH-SY5Y cell inflammation, oxidative stress, and oxidative defense gene expression; however, these resveratrol protective effects are affected by AMPK antagonists (Compounds C) blocking. These findings improve our understanding of the mechanism of the AMPK-dependent protective effect of resveratrol under 3D OGD-induced inflammation and oxidative stress-mediated cerebral ischemic stroke conditions. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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Review

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16 pages, 1362 KiB

Open AccessReview

Crosstalk of Mast Cells and Natural Killer Cells with Neurons in Chemotherapy-Induced Peripheral Neuropathy

by Hyun Don Yun, Yugal Goel and Kalpna Gupta

Int. J. Mol. Sci. 2023, 24(16), 12543; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612543 - 08 Aug 2023

Cited by 2 | Viewed by 1508

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major comorbidity of cancer. Multiple clinical interventions have been studied to effectively treat CIPN, but the results have been disappointing, with no or little efficacy. Hence, understanding the pathophysiology of CIPN is critical to improving the quality of life and clinical outcomes of cancer patients. Although various mechanisms of CIPN have been described in neuropathic anti-cancer agents, the neuroinflammatory process involving cytotoxic/proinflammatory immune cells remains underexamined. While mast cells (MCs) and natural killer (NK) cells are the key innate immune compartments implicated in the pathogenesis of peripheral neuropathy, their role in CIPN has remained under-appreciated. Moreover, the biology of proinflammatory cytokines associated with MCs and NK cells in CIPN is particularly under-evaluated. In this review, we will focus on the interactions between MCs, NK cells, and neuronal structure and their communications via proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in peripheral neuropathy in association with tumor immunology. This review will help lay the foundation to investigate MCs, NK cells, and cytokines to advance future therapeutic strategies for CIPN. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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23 pages, 4282 KiB

Open AccessReview

Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage

by Mara Verónica Millán Solano, Citlaltepetl Salinas Lara, Carlos Sánchez-Garibay, Luis O. Soto-Rojas, Itzel Escobedo-Ávila, Martha Lilia Tena-Suck, Rocío Ortíz-Butrón, José Alberto Choreño-Parra, José Pablo Romero-López and María Estela Meléndez Camargo

Int. J. Mol. Sci. 2023, 24(15), 11902; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241511902 - 25 Jul 2023

Cited by 2 | Viewed by 2401

Abstract

Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood–brain barrier’s (BBB´s) and blood–cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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30 pages, 901 KiB

Open AccessReview

Central and Peripheral Inflammation: A Common Factor Causing Addictive and Neurological Disorders and Aging-Related Pathologies

by Angélica P. Escobar, Christian Bonansco, Gonzalo Cruz, Alexies Dagnino-Subiabre, Marco Fuenzalida, Ignacio Negrón, Ramón Sotomayor-Zárate, Jonathan Martínez-Pinto and Gonzalo Jorquera

Int. J. Mol. Sci. 2023, 24(12), 10083; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210083 - 13 Jun 2023

Cited by 1 | Viewed by 2937

Abstract

Many diseases and degenerative processes affecting the nervous system and peripheral organs trigger the activation of inflammatory cascades. Inflammation can be triggered by different environmental conditions or risk factors, including drug and food addiction, stress, and aging, among others. Several pieces of evidence show that the modern lifestyle and, more recently, the confinement associated with the COVID-19 pandemic have contributed to increasing the incidence of addictive and neuropsychiatric disorders, plus cardiometabolic diseases. Here, we gather evidence on how some of these risk factors are implicated in activating central and peripheral inflammation contributing to some neuropathologies and behaviors associated with poor health. We discuss the current understanding of the cellular and molecular mechanisms involved in the generation of inflammation and how these processes occur in different cells and tissues to promote ill health and diseases. Concomitantly, we discuss how some pathology-associated and addictive behaviors contribute to worsening these inflammation mechanisms, leading to a vicious cycle that promotes disease progression. Finally, we list some drugs targeting inflammation-related pathways that may have beneficial effects on the pathological processes associated with addictive, mental, and cardiometabolic illnesses. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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16 pages, 914 KiB

Open AccessReview

The Potential Benefits of Quercetin for Brain Health: A Review of Anti-Inflammatory and Neuroprotective Mechanisms

by Ming-Chang Chiang, Tsung-Yu Tsai and Chieh-Ju Wang

Int. J. Mol. Sci. 2023, 24(7), 6328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076328 - 28 Mar 2023

Cited by 20 | Viewed by 5168

Abstract

Neuroinflammation is a critical factor in developing and progressing numerous brain diseases, including neurodegenerative diseases. Chronic or excessive neuroinflammation can lead to neurotoxicity, causing brain damage and contributing to the onset and progression of various brain diseases. Therefore, understanding neuroinflammation mechanisms and developing strategies to control them is crucial for treating brain diseases. Studies have shown that neuroinflammation plays a vital role in the progression of neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD), and stroke. Additionally, the effects of PM_2.5 pollution on the brain, including neuroinflammation and neurotoxicity, are well-documented. Quercetin is a flavonoid, a plant pigment in many fruits, vegetables, and grains. Quercetin has been studied for its potential health benefits, including its anti-inflammatory, antioxidant, and anti-cancer properties. Quercetin may also have a positive impact on immune function and allergy symptoms. In addition, quercetin has been shown to have anti-inflammatory and neuroprotective properties and can activate AMP-activated protein kinase (AMPK), a cellular energy sensor that modulates inflammation and oxidative stress. By reducing inflammation and protecting against neuroinflammatory toxicity, quercetin holds promise as a safe and effective adjunctive therapy for treating neurodegenerative diseases and other brain disorders. Understanding and controlling the mechanisms of NF-κB and NLRP3 inflammasome pathways are crucial for preventing and treating conditions, and quercetin may be a promising tool in this effort. This review article aims to discuss the role of neuroinflammation in the development and progression of various brain disorders, including neurodegenerative diseases and stroke, and the impact of PM_2.5 pollution on the brain. The paper also highlights quercetin’s potential health benefits and anti-inflammatory and neuroprotective properties. Full article

(This article belongs to the Special Issue Neuroinflammation Toxicity and Neuroprotection)

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