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Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2
In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9486307/ https://www.ncbi.nlm.nih.gov/pubmed/36147353 http://dx.doi.org/10.3389/fphar.2022.972828 |
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author | Shen, Baoyu Zhang, Ruilin Yang, Genmeng Peng, Yanxia Nie, Qianyun Yu, Hao Dong, Wenjuan Chen, Bingzheng Song, Chunhui Tian, Yan Qin, Lixiang Shu, Junjie Hong, Shijun Li, Lihua |
author_facet | Shen, Baoyu Zhang, Ruilin Yang, Genmeng Peng, Yanxia Nie, Qianyun Yu, Hao Dong, Wenjuan Chen, Bingzheng Song, Chunhui Tian, Yan Qin, Lixiang Shu, Junjie Hong, Shijun Li, Lihua |
author_sort | Shen, Baoyu |
collection | PubMed |
description | In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH use disorders. Cannabidiol (CBD), a major non-psychoactive (and non-addictive) cannabinoid from the cannabis plant, shows neuroprotective, antioxidative, and anti-inflammatory properties under METH exposure. At present, however, the mechanisms underlying these properties remain unclear, which continues to hinder research on its therapeutic potential. In the current study, computational simulations showed that CBD and METH may directly bind to the dopamine receptor D1 (DRD1) via two overlapping binding sites. Moreover, CBD may compete with METH for the PHE-313 binding site. We also found that METH robustly induced apoptosis with activation of the caspase-8/caspase-3 cascade in-vitro and in-vivo, while CBD pretreatment prevented these changes. Furthermore, METH increased the expression of DRD1, phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) at serine 421 (Ser421), and level of intracellular Ca(2+) in-vitro and in-vivo, but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca(2+) overload in-vitro. In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca(2+) overload, which were blocked by CBD pretreatment in-vitro. These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca(2+) signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding. |
format | Online Article Text |
id | pubmed-9486307 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94863072022-09-21 Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 Shen, Baoyu Zhang, Ruilin Yang, Genmeng Peng, Yanxia Nie, Qianyun Yu, Hao Dong, Wenjuan Chen, Bingzheng Song, Chunhui Tian, Yan Qin, Lixiang Shu, Junjie Hong, Shijun Li, Lihua Front Pharmacol Pharmacology In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH use disorders. Cannabidiol (CBD), a major non-psychoactive (and non-addictive) cannabinoid from the cannabis plant, shows neuroprotective, antioxidative, and anti-inflammatory properties under METH exposure. At present, however, the mechanisms underlying these properties remain unclear, which continues to hinder research on its therapeutic potential. In the current study, computational simulations showed that CBD and METH may directly bind to the dopamine receptor D1 (DRD1) via two overlapping binding sites. Moreover, CBD may compete with METH for the PHE-313 binding site. We also found that METH robustly induced apoptosis with activation of the caspase-8/caspase-3 cascade in-vitro and in-vivo, while CBD pretreatment prevented these changes. Furthermore, METH increased the expression of DRD1, phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) at serine 421 (Ser421), and level of intracellular Ca(2+) in-vitro and in-vivo, but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca(2+) overload in-vitro. In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca(2+) overload, which were blocked by CBD pretreatment in-vitro. These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca(2+) signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding. Frontiers Media S.A. 2022-09-06 /pmc/articles/PMC9486307/ /pubmed/36147353 http://dx.doi.org/10.3389/fphar.2022.972828 Text en Copyright © 2022 Shen, Zhang, Yang, Peng, Nie, Yu, Dong, Chen, Song, Tian, Qin, Shu, Hong and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Shen, Baoyu Zhang, Ruilin Yang, Genmeng Peng, Yanxia Nie, Qianyun Yu, Hao Dong, Wenjuan Chen, Bingzheng Song, Chunhui Tian, Yan Qin, Lixiang Shu, Junjie Hong, Shijun Li, Lihua Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title | Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title_full | Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title_fullStr | Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title_full_unstemmed | Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title_short | Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2 |
title_sort | cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor d1-mediated calcium-dependent phosphorylation of methyl-cpg-binding protein 2 |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9486307/ https://www.ncbi.nlm.nih.gov/pubmed/36147353 http://dx.doi.org/10.3389/fphar.2022.972828 |
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