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
Key Laboratory of Drug Addiction Medicine of National Health Commission (NHC), School of Forensic Medicine, Kunming Medical University, Kunming, China.
Front Pharmacol. 2022 Sep 6;13:972828. doi: 10.3389/fphar.2022.972828. eCollection 2022.
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 and , 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 and , but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca overload . In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca overload, which were blocked by CBD pretreatment . These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding.
在过去十年中，甲基苯丙胺（METH）滥用在美国、东亚和东南亚地区急剧增加。METH滥用不仅会导致严重的药物依赖，还会产生不可逆的神经毒性。目前，尚无批准用于治疗METH使用障碍的药物疗法。大麻二酚（CBD）是大麻植物中的一种主要非精神活性（且非成瘾性）大麻素，在METH暴露下具有神经保护、抗氧化和抗炎特性。然而，目前这些特性背后的机制仍不清楚，这继续阻碍着对其治疗潜力的研究。在当前的研究中，计算模拟表明CBD和METH可能通过两个重叠的结合位点直接与多巴胺受体D1（DRD1）结合。此外，CBD可能与METH竞争PHE-313结合位点。我们还发现，METH通过激活半胱天冬酶-8/半胱天冬酶-3级联反应强烈诱导细胞凋亡，而CBD预处理可防止这些变化。此外，METH增加了DRD1的表达、丝氨酸421（Ser421）处甲基化CpG结合蛋白2（MeCP2）的磷酸化以及细胞内Ca的水平，但这些作用被CBD预处理所阻断。DRD1拮抗剂SCH23390显著预防了METH诱导的细胞凋亡、MeCP2磷酸化和Ca超载。相反，DRD1激动剂SKF81297显著增加了细胞凋亡、MeCP2磷酸化和Ca超载，而CBD预处理可阻断这些作用。这些结果表明，CBD通过调节DRD1介导的MeCP2磷酸化和Ca信号传导来预防METH诱导的神经毒性。这项研究表明，CBD预处理可能通过竞争性结合来抵抗METH对DRD1的影响。
