Neurotoxicity: Mechanisms and Potential Therapeutic Strategies (Closed)

A topical collection in Biomedicines (ISSN 2227-9059). This collection belongs to the section "Neurobiology and Clinical Neuroscience".

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Collection Editor
Department of Pharmacology & Physiology, School of Biomedical Science, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107-1898, USA
Interests: pancreatic cancer; environmental toxicants; mitochondrial toxicity; apoptosis; cellular regulation; tryptophan-kynurenine pathway; indoleamine 2,3-dioxygenase
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

We are constantly subjected to toxic insults, most of these insults going unnoticed. Whether it is the environment, occupational or intentional exposure, toxicants are a part of our daily lives. As we go through the day, exposure to toxic metals, chemical by-products, particulate matter, volatile gases, pesticides, etc., occurs constantly. In most instances, this exposure is at a very low level, but continues for an extended time. With chronic exposure, we slowly build deficits, such as a loss of free radical scavenging enzymes, altered protein production and epigenetic changes. Collectively leading to signs and symptoms of neurotoxicity. The intent of this Topical Collection is the discuss mechanisms leading to neurotoxicity, and from these mechanisms, what potential therapeutic strategies are being developed. We would like to bring together a diverse group who are examining many different perspectives of neurotoxicity along with groups developing therapeutics to alleviate or prevent these toxic insults.

Prof. David R Wallace
Collection Editor

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Keywords

  • Astrocytes
  • Microglia
  • Neuroinflammation
  • Neurodegeneration
  • Oxidative Stress
  • protein degeneration
  • heavy metals
  • pesticides

Published Papers (4 papers)

2022

Jump to: 2021, 2020, 2019

20 pages, 4233 KiB  
Article
Increases of Phosphorylated Tau (Ser202/Thr205) in the Olfactory Regions Are Associated with Impaired EEG and Olfactory Behavior in Traumatic Brain Injury Mice
by Younghyun Yoon, SuHyun Kim, YunHee Seol, Hyoenjoo Im, Uiyeol Park, Hio-Been Han, Jee Hyun Choi and Hoon Ryu
Biomedicines 2022, 10(4), 865; https://doi.org/10.3390/biomedicines10040865 - 7 Apr 2022
Cited by 1 | Viewed by 2349
Abstract
Traumatic brain injury (TBI) leads to long-term cognitive impairments, with an increased risk for neurodegenerative and psychiatric disorders. Among these various impairments, olfactory dysfunction is one of the most common symptoms in TBI patients. However, there are very few studies that show the [...] Read more.
Traumatic brain injury (TBI) leads to long-term cognitive impairments, with an increased risk for neurodegenerative and psychiatric disorders. Among these various impairments, olfactory dysfunction is one of the most common symptoms in TBI patients. However, there are very few studies that show the association between olfactory dysfunction and repetitive TBI. To investigate the effects of repetitive TBI on olfactory functioning and the related pathological neuronal injuries in mice, we applied a weight-drop model of TBI and performed neuropathological examinations and electroencephalography (EEG) in olfactory-bulb-associated areas. Through neuropathological examinations, we found significant increases of amyloid precursor protein (APP) and phosphorylated Tau (p-Tau) (S202/T205) in olfactory-bulb-associated areas. Neuronal atrophy in the lateral anterior olfactory nucleus (AOL), granule layer olfactory bulb (GrO), and dorsal tenia tecta (DTT) was also found to be correlated with p-Tau levels. However, there was no difference in the total Tau levels in the olfactory-bulb-associated areas of TBI mice. Electroencephalography (EEG) of repetitive TBI mouse models showed impaired spontaneous delta oscillation, as well as altered cross-frequency coupling between delta phase and amplitudes of the fast oscillations in the resting-state olfactory bulb. Furthermore, abnormal alterations in EEG band powers were observed during the olfactory oddball paradigm test. TBI also led to impairments of the olfactory-function-associated behaviors. This study provides evidence of behavioral, neuropathological, and physiological alterations in the mouse olfactory system caused by repetitive TBI. Together, p-Tau alterations and EEG impairments may serve as important biomarkers of olfactory-track-associated dysfunctions in repetitive TBI. Full article
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2021

Jump to: 2022, 2020, 2019

18 pages, 2769 KiB  
Article
Cannabidiol Selectively Binds to the Voltage-Gated Sodium Channel Nav1.4 in Its Slow-Inactivated State and Inhibits Sodium Current
by Chiung-Wei Huang, Pi-Chen Lin, Jian-Lin Chen and Ming-Jen Lee
Biomedicines 2021, 9(9), 1141; https://doi.org/10.3390/biomedicines9091141 - 2 Sep 2021
Cited by 9 | Viewed by 2390
Abstract
Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The [...] Read more.
Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The binding affinity of CBD to the channel was evaluated using whole-cell recording. The CDOCKER program was employed to model CBD docking onto the Nav1.4 channel to determine its binding sites. Our results revealed no differential inhibition of sodium current by CBD when the channels were in activation or fast inactivation status. However, differential inhibition was observed with a dose-dependent manner after a prolonged period of depolarization, leaving the channel in a slow-inactivated state. Moreover, CBD binds selectively to the slow-inactivated state with a significantly faster binding kinetics (>64,000 M−1 s−1) and a higher affinity (Kd of fast inactivation vs. slow-inactivation: >117.42 μM vs. 51.48 μM), compared to the fast inactivation state. Five proposed CBD binding sites in a bundle crossing region of the Nav1.4 channels pore was identified as Val793, Leu794, Phe797, and Cys759 in domain I/S6, and Ile1279 in domain II/S6. Our findings imply that CBD favorably binds to the Nav1.4 channel in its slow-inactivated state. Full article
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2020

Jump to: 2022, 2021, 2019

21 pages, 1488 KiB  
Review
Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder
by Davide Ravaccia and Taravat Ghafourian
Biomedicines 2020, 8(12), 557; https://doi.org/10.3390/biomedicines8120557 - 1 Dec 2020
Cited by 21 | Viewed by 4189
Abstract
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterised by impairments in communication, social interaction, and the presence of restrictive and repetitive behaviours. Over the past decade, most of the research in ASD has focused on the contribution of genetics, with [...] Read more.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterised by impairments in communication, social interaction, and the presence of restrictive and repetitive behaviours. Over the past decade, most of the research in ASD has focused on the contribution of genetics, with the identification of a variety of different genes and mutations. However, the vast heterogeneity in clinical presentations associated with this disorder suggests that environmental factors may be involved, acting as a “second hit” in already genetically susceptible individuals. To this regard, emerging evidence points towards a role for maternal immune system dysfunctions. This literature review considered evidence from epidemiological studies and aimed to discuss the pathological relevance of the maternal immune system in ASD by looking at the proposed mechanisms by which it alters the prenatal environment. In particular, this review focuses on the effects of maternal immune activation (MIA) by looking at foetal brain-reactive antibodies, cytokines and the microbiome. Despite the arguments presented here that strongly implicate MIA in the pathophysiology of ASD, further research is needed to fully understand the precise mechanisms by which they alter brain structure and behaviour. Overall, this review has not only shown the importance of the maternal immune system as a risk factor for ASD, but more importantly, has highlighted new promising pathways to target for the discovery of novel therapeutic interventions for the treatment of such a life-changing disorder. Full article
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2019

Jump to: 2022, 2021, 2020

16 pages, 2045 KiB  
Article
Comprehensive Analysis of Neurotoxin-Induced Ablation of Dopaminergic Neurons in Zebrafish Larvae
by Michael Kalyn, Khang Hua, Suzita Mohd Noor, Chee Ern David Wong and Marc Ekker
Biomedicines 2020, 8(1), 1; https://doi.org/10.3390/biomedicines8010001 - 28 Dec 2019
Cited by 28 | Viewed by 5497
Abstract
Neurotoxin exposure of zebrafish larvae has been used to mimic a Parkinson’s disease (PD) phenotype and to facilitate high-throughput drug screening. However, the vulnerability of zebrafish to various neurotoxins was shown to be variable. Here, we provide a direct comparison of ablative effectiveness [...] Read more.
Neurotoxin exposure of zebrafish larvae has been used to mimic a Parkinson’s disease (PD) phenotype and to facilitate high-throughput drug screening. However, the vulnerability of zebrafish to various neurotoxins was shown to be variable. Here, we provide a direct comparison of ablative effectiveness in order to identify the optimal neurotoxin-mediated dopaminergic (DAnergic) neuronal death in larval zebrafish. Transgenic zebrafish, Tg(dat:eGFP), were exposed to different concentrations of the neurotoxins MPTP, MPP+, paraquat, 6-OHDA, and rotenone for four days, starting at three days post-fertilization. The LC50 of each respective neurotoxin concentration was determined. Confocal live imaging on Tg(dat:eGFP) showed that MPTP, MPP+, and rotenone caused comparable DAnergic cell loss in the ventral diencephalon (vDC) region while, paraquat and 6-OHDA caused fewer losses of DAnergic cells. These results were further supported by respective gene expression analyses of dat, th, and p53. Importantly, the loss of DAnergic cells from exposure to MPTP, MPP+, and rotenone impacted larval locomotor function. MPTP induced the largest motor deficit, but this was accompanied by the most severe morphological impairment. We conclude that, of the tested neurotoxins, MPP+ recapitulates a substantial degree of DAnergic ablation and slight locomotor perturbations without systemic defects indicative of a Parkinsonian phenotype. Full article
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