2. Academic Validation
  3. Salvinorin A ameliorates pilocarpine-induced seizures by regulating hippocampal microglia polarization

Salvinorin A ameliorates pilocarpine-induced seizures by regulating hippocampal microglia polarization

  • J Ethnopharmacol. 2024 Dec 5:335:118697. doi: 10.1016/j.jep.2024.118697.
Jiao Yang 1,  Ji-Heng Cai 2,  Tong-Xuan Wu 3,  Zhi-Qiang Gao 4,  Chao Zhou 3,  Qi Wu 5,  Miao-Jin Ji 6
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: cjhtop1@163.com.
  • 3 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.
  • 4 School of Pharmacology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 5 Department of Physiology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 6 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. Electronic address: 100002018061@xzhmu.edu.cn.
PMID: 39154669 DOI: 10.1016/j.jep.2024.118697
Abstract

Ethnopharmacological relevance: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Epilepsy; Kappa opioid receptor; Microglia polarization; Salvinorin A.

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