Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China; Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200030, China.
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China; Department of Anesthesiology, Sheyang County People's Hospital, Yancheng, 224300, China.
J Ethnopharmacol. 2024 Dec 5;335:118697. doi: 10.1016/j.jep.2024.118697. Epub 2024 Aug 16.
Salvia divinorum (Epling and Játiva) is a psychoactive plant traditionally used by the Latinos for various medicinal purposes. Salvinorin A (Sal A), the main bioactive constituent of S. divinorum, is a natural highly selective kappa opioid receptor (KOR) agonist. Considering the anti-inflammatory effect of S. divinorum and endogenous hippocampal dynorphin/kappa opioid receptor (KOR) system playing an anticonvulsant function, we hypothesis that Sal A can be a potential candidate to treat epilepsy. Here, we identified whether Sal A ameliorated epileptic seizures and neuronal damages in animal model and in vitro model and investigated its underlying mechanisms.
Mice epilepsy model was induced by pilocarpine following seizures assessed by Racine classification. Hippocampus tissues were obtained for genetic, protein, and histological investigation. Furthermore, lipopolysaccharide (LPS)-activated BV2 microglial cells were utilized to validate the anti-inflammatory and microglia polarization regulation effects of Sal A.
Sal A treatment significantly prolonged the latency to status epileptics (SE) and shortened the duration of SE in the pilocarpine-induced model. It also alleviated neuronal damages via activation of the AMPK/JNK/p-38 MAPK pathway and inhibition of apoptosis-related protein in hippocampus tissues. Furthermore, Sal A dose-dependently reduced microglia-mediated expression of pro-inflammatory cytokines and increased anti-inflammatory factors levels in SE mice and LPS-activated BV2 microglial cells by regulating microglia polarization. In addition, the effect of Sal A in vitro was totally blocked by KOR antagonist nor-BNI.
Sal A treatment protects against epileptic seizures and neuronal damages in pilocarpine-induced models by suppressing the inflammation response through regulating microglial M1/M2 polarization. This study might serve as a theoretical basis for clinical applications of Sal A and its analogs and provide a new insight into the development of anti-seizure drugs.
迷幻鼠尾草（Epling 和 Játiva）是一种具有精神活性的植物，传统上被拉丁裔人用于各种医疗用途。Salvinorin A（Sal A）是迷幻鼠尾草的主要生物活性成分，是一种天然的高度选择性κ阿片受体（KOR）激动剂。鉴于迷幻鼠尾草的抗炎作用以及内源性海马 dynorphin/kappa 阿片受体（KOR）系统发挥抗惊厥作用，我们假设 Sal A 可能是治疗癫痫的潜在候选药物。在这里，我们确定了 Sal A 是否能改善动物模型和体外模型中的癫痫发作和神经元损伤，并研究了其潜在机制。
匹罗卡品诱导癫痫发作后，通过 Racine 分类评估癫痫发作模型，然后用 Sal A 进行治疗。从海马组织中获取遗传、蛋白质和组织学研究。此外，利用脂多糖（LPS）激活的 BV2 小胶质细胞验证 Sal A 的抗炎和小胶质细胞极化调节作用。
Sal A 治疗可显著延长匹罗卡品诱导模型的癫痫发作潜伏期并缩短癫痫持续时间。它还通过激活 AMPK/JNK/p-38 MAPK 通路和抑制海马组织中凋亡相关蛋白来减轻神经元损伤。此外，Sal A 剂量依赖性地降低了 SE 小鼠和 LPS 激活的 BV2 小胶质细胞中小胶质细胞介导的促炎细胞因子的表达，并通过调节小胶质细胞极化增加抗炎因子水平。此外，Sal A 在体外的作用完全被 KOR 拮抗剂 nor-BNI 阻断。
Sal A 通过调节小胶质细胞 M1/M2 极化抑制炎症反应，对匹罗卡品诱导的模型中的癫痫发作和神经元损伤起到保护作用。这项研究可能为 Sal A 及其类似物的临床应用提供理论依据，并为抗癫痫药物的开发提供新的思路。
