{"title":"大麻二酚通过调节瞬时受体电位香草样1型减轻甲基苯丙胺诱导的氧化神经毒性","authors":"Baoyu Shen , Genmeng Yang , Mengran Lv, Zhenling Wu, Yuan Zhang, Yuanyuan Cao, Junjie Shu, Wenjuan Dong, Zhenping Hou, Di Jing, Jing Xu, Yuhan Hou, Xinjie Zhang, Shijun Hong, Lihua Li","doi":"10.1016/j.phymed.2025.157015","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.</div></div><div><h3>Purpose</h3><div>This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.</div></div><div><h3>Results</h3><div>In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca<sup>2+</sup> overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca<sup>2+</sup> influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca<sup>2+</sup> influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca<sup>2+</sup> overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.</div></div><div><h3>Conclusion</h3><div>METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca<sup>2+</sup> influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 157015"},"PeriodicalIF":6.7000,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1\",\"authors\":\"Baoyu Shen , Genmeng Yang , Mengran Lv, Zhenling Wu, Yuan Zhang, Yuanyuan Cao, Junjie Shu, Wenjuan Dong, Zhenping Hou, Di Jing, Jing Xu, Yuhan Hou, Xinjie Zhang, Shijun Hong, Lihua Li\",\"doi\":\"10.1016/j.phymed.2025.157015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.</div></div><div><h3>Purpose</h3><div>This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.</div></div><div><h3>Results</h3><div>In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca<sup>2+</sup> overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca<sup>2+</sup> influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca<sup>2+</sup> influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca<sup>2+</sup> overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.</div></div><div><h3>Conclusion</h3><div>METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca<sup>2+</sup> influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.</div></div>\",\"PeriodicalId\":20212,\"journal\":{\"name\":\"Phytomedicine\",\"volume\":\"145 \",\"pages\":\"Article 157015\"},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2025-06-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Phytomedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0944711325006543\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325006543","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1
Background
The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.
Purpose
This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.
Results
In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca2+ overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca2+ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca2+ overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.
Conclusion
METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca2+ influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.
期刊介绍:
Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.