Wuhan Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
Wuhan Mental Health Center, Wuhan, China.
J Food Biochem. 2021 Feb;45(2):e13622. doi: 10.1111/jfbc.13622. Epub 2021 Jan 27.
Methamphetamine (METH) abuse produces serious neurotoxicity to the central nervous system along with long-term cognitive dysfunction. Resveratrol, a natural polyphenol, has broad application prospects in the treatment of neurodegenerative diseases. Therefore, this study was conducted to investigate whether resveratrol might alleviate METH-induced memory deficits in vivo. We found that multiple exposures to METH significantly impaired cognitive functions and caused long-lasting memory deficits (p < .05). Pretreatment of resveratrol (10 or 100 mg/kg) remarkably attenuated METH-induced memory impairment in mice (p < .05). Bioinformatics analysis results showed that resveratrol might alleviate memory deficits by inhibiting METH-induced oxidative damage and apoptosis. Molecular docking showed that resveratrol had hydrogen bonding interactions with Kelch-like ECH associated protein 1 (Keap1), a repressor protein of the classic antioxidant Keap1-Nrf2 pathway. Further results validated oxidative stress parameters, apoptosis, and expression of Keap1 were significantly increased, while the translocation and activation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and expression of its downstream proteins were greatly decreased in the hippocampus after METH exposure (p < .05). These changes caused by METH could be prevented by resveratrol (p < .05). Therefore, these findings suggested that the prevention of resveratrol on memory dysfunction induced by METH was possibly related to the activation of the Keap1-Nrf2 pathway and reduction of apoptosis. Supplementation of resveratrol could be a potential treatment for preventing the neurotoxicity of METH in the future. PRACTICAL APPLICATIONS: As one of the worst commonly abused psychostimulants, methamphetamine (METH) addiction produces serious complications including cognitive impairment and memory deficits. Resveratrol is a natural polyphenol that has important nutritional supplements and protective effects in the treatment of many neurodegenerative diseases. In this study, the results of bioinformatics prediction and experimental validation showed that resveratrol might effectively prevent memory impairment via the interaction with Keap1, activation of the Keap1-Nrf2 pathway, and inhibition of DNA damage and apoptotic responses post METH exposure. Therefore, these findings provide new ideas and insights into the application of resveratrol in the treatment of nervous system damage caused by METH.
标题：白藜芦醇通过抑制 KEAP1-Nrf2 通路减轻 methamphetamine 诱导的小鼠认知功能障碍
摘要： 甲基苯丙胺（METH）滥用会对中枢神经系统造成严重的神经毒性，同时伴有长期认知功能障碍。白藜芦醇是一种天然多酚，在治疗神经退行性疾病方面具有广泛的应用前景。因此，本研究旨在探讨白藜芦醇是否可能减轻体内 METH 诱导的记忆障碍。我们发现，多次暴露于 METH 可显著损害认知功能并导致长期记忆障碍（p<0.05）。白藜芦醇（10 或 100mg/kg）预处理可显著减轻 METH 诱导的小鼠记忆障碍（p<0.05）。生物信息学分析结果表明，白藜芦醇可能通过抑制 METH 诱导的氧化损伤和细胞凋亡来减轻记忆障碍。分子对接表明，白藜芦醇与 Kelch-like ECH 相关蛋白 1（Keap1）具有氢键相互作用，Keap1 是经典抗氧化剂 Keap1-Nrf2 通路的抑制蛋白。进一步的结果验证了氧化应激参数、细胞凋亡以及 Keap1 的表达在 METH 暴露后明显增加，而核因子红细胞 2 相关因子 2（Nrf2）向核内的易位和其下游蛋白的表达则显著降低（p<0.05）。这些由 METH 引起的变化可以被白藜芦醇预防（p<0.05）。因此，这些发现表明，白藜芦醇对 METH 诱导的记忆功能障碍的预防可能与 Keap1-Nrf2 通路的激活和细胞凋亡的减少有关。补充白藜芦醇可能是未来预防 METH 神经毒性的一种潜在治疗方法。
实际应用：作为最严重的滥用精神兴奋剂之一，甲基苯丙胺（METH）成瘾会产生严重的并发症，包括认知障碍和记忆缺陷。白藜芦醇是一种天然多酚，在治疗许多神经退行性疾病方面具有重要的营养补充和保护作用。在这项研究中，生物信息学预测和实验验证的结果表明，白藜芦醇可能通过与 Keap1 相互作用、激活 Keap1-Nrf2 通路以及抑制 METH 暴露后的 DNA 损伤和凋亡反应，有效预防记忆障碍。因此，这些发现为白藜芦醇在治疗 METH 引起的神经系统损伤中的应用提供了新的思路和见解。
