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JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway

Parkinson’s disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in the substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) is a common and widely used pesticide which can directly...

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Autores principales: Zou, Lu, Che, Zhen, Ding, Kun, Zhang, Chao, Liu, Xia, Wang, Luman, Li, Aiping, Zhou, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215424/
https://www.ncbi.nlm.nih.gov/pubmed/37238000
http://dx.doi.org/10.3390/antiox12051134
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author Zou, Lu
Che, Zhen
Ding, Kun
Zhang, Chao
Liu, Xia
Wang, Luman
Li, Aiping
Zhou, Jianwei
author_facet Zou, Lu
Che, Zhen
Ding, Kun
Zhang, Chao
Liu, Xia
Wang, Luman
Li, Aiping
Zhou, Jianwei
author_sort Zou, Lu
collection PubMed
description Parkinson’s disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in the substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) is a common and widely used pesticide which can directly inhibit mitochondrial complex I, leading to a loss of dopaminergic neurons. Our previous studies proved that the JWA gene (arl6ip5) may play a prominent role in resisting aging, oxidative stress and inflammation, and JWA knockout in astrocytes increases the susceptibility of mice to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. JWA-activating compound 4 (JAC4) is a small-molecule activator of the JWA gene, but its role in and mechanism against PD have not yet been clarified. In the present study, we showed that the JWA expression level is strongly related to tyrosine hydroxylase (TH) in different growth periods of mice. Additionally, we constructed models with Rot in vivo and in vitro to observe the neuroprotective effects of JAC4. Our results demonstrated that JAC4 prophylactic intervention improved motor dysfunction and dopaminergic neuron loss in mice. Mechanistically, JAC4 reduced oxidative stress damage by reversing mitochondrial complex I damage, reducing nuclear factor kappa-B (NF-κB) translocation and repressing nucleotide-binding domain, leucine-rich-containing family and pyrin domain-containing-3 (NLRP3) inflammasome activation. Overall, our results provide proof that JAC4 could serve as a novel effective agent for PD prevention.
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spelling pubmed-102154242023-05-27 JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway Zou, Lu Che, Zhen Ding, Kun Zhang, Chao Liu, Xia Wang, Luman Li, Aiping Zhou, Jianwei Antioxidants (Basel) Article Parkinson’s disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in the substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) is a common and widely used pesticide which can directly inhibit mitochondrial complex I, leading to a loss of dopaminergic neurons. Our previous studies proved that the JWA gene (arl6ip5) may play a prominent role in resisting aging, oxidative stress and inflammation, and JWA knockout in astrocytes increases the susceptibility of mice to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. JWA-activating compound 4 (JAC4) is a small-molecule activator of the JWA gene, but its role in and mechanism against PD have not yet been clarified. In the present study, we showed that the JWA expression level is strongly related to tyrosine hydroxylase (TH) in different growth periods of mice. Additionally, we constructed models with Rot in vivo and in vitro to observe the neuroprotective effects of JAC4. Our results demonstrated that JAC4 prophylactic intervention improved motor dysfunction and dopaminergic neuron loss in mice. Mechanistically, JAC4 reduced oxidative stress damage by reversing mitochondrial complex I damage, reducing nuclear factor kappa-B (NF-κB) translocation and repressing nucleotide-binding domain, leucine-rich-containing family and pyrin domain-containing-3 (NLRP3) inflammasome activation. Overall, our results provide proof that JAC4 could serve as a novel effective agent for PD prevention. MDPI 2023-05-20 /pmc/articles/PMC10215424/ /pubmed/37238000 http://dx.doi.org/10.3390/antiox12051134 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zou, Lu
Che, Zhen
Ding, Kun
Zhang, Chao
Liu, Xia
Wang, Luman
Li, Aiping
Zhou, Jianwei
JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title_full JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title_fullStr JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title_full_unstemmed JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title_short JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway
title_sort jac4 alleviates rotenone-induced parkinson’s disease through the inactivation of the nlrp3 signal pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215424/
https://www.ncbi.nlm.nih.gov/pubmed/37238000
http://dx.doi.org/10.3390/antiox12051134
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