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

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-22 DOI:10.1016/j.phymed.2025.157015

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

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引用次数: 0

摘要

背景：在世界许多地区，甲基苯丙胺（冰毒）滥用的流行率显著上升。尽管有这种增加，但与冰毒相关的神经毒性的复杂性还没有得到充分的了解。大麻二酚（Cannabidiol， CBD）是大麻中的一种非成瘾性植物成分，已被用于临床前和临床研究，用于治疗各种神经精神疾病，但CBD发挥治疗作用的机制尚不清楚。目的探讨甲基苯丙胺暴露下瞬时受体电位香草样蛋白1 （TRPV1）介导氧化性神经毒性的机制，揭示CBD对甲基苯丙胺氧化性神经毒性的治疗靶点。结果与对照组相比，甲基安非他命服毒者海马和内侧前额叶皮层TRPV1过度激活、细胞内Ca2+超载、氧化应激增加、细胞凋亡升高。分子对接和表面等离子体共振（SPR）检测结果表明，CBD与人TRPV1结合。此外，甲基苯甲胺诱导HT-22细胞中的Ca2+内流、氧化应激、细胞损伤和TRPV1激活，这些都可以通过TRPV1敲除或CBD预处理来缓解。CBD预处理也阻断了TRPV1激动剂辣椒素诱导的Ca2+内流、氧化应激、细胞损伤和HT-22细胞中TRPV1的激活。此外，甲基安非他明还会引发小鼠海马的刻板行为、空间记忆障碍、TRPV1激活、Ca2+超载、细胞凋亡和氧化应激，而CBD预处理可以减轻这些影响。最后，海马体TRPV1敲低可减少甲基醚诱导的小鼠刻板行为和空间记忆障碍，阻断甲基醚诱导的小鼠海马细胞凋亡和氧化应激。结论甲基安非他明通过激活TRPV1依赖的Ca2+内流、氧化应激和细胞凋亡诱导氧化神经毒性，而CBD通过调节TRPV1抑制甲基安非他明诱导的氧化神经毒性。本研究确立了CBD作为甲基苯丙胺使用障碍的治疗干预措施。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1

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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.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

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.