2. Academic Validation
  3. Oridonin exerts anticonvulsant profile and neuroprotective activity in epileptic mice by inhibiting NLRP3-mediated pyroptosis

Oridonin exerts anticonvulsant profile and neuroprotective activity in epileptic mice by inhibiting NLRP3-mediated pyroptosis

  • Int Immunopharmacol. 2024 Jun 15:134:112247. doi: 10.1016/j.intimp.2024.112247.
Ting Zhao 1,  Xuefei Zhang 1,  Xiaoxiao Cui 1,  Songxue Su 1,  Lei Li 1,  Yanan Chen 1,  Na Wang 1,  Lei Sun 1,  Jianyuan Zhao 2,  Jiewen Zhang 3,  Xiong Han 4,  Jing Cao 5
Affiliations

Affiliations

  • 1 Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
  • 2 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: zhaojy@vip.163.com.
  • 3 Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: zhangjiewen@zzu.edu.cn.
  • 4 Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: hanxiong@zzu.edu.cn.
  • 5 Department of Neurology and Basic Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China. Electronic address: caojing@zzu.edu.cn.
PMID: 38759374 DOI: 10.1016/j.intimp.2024.112247
Abstract

Background: Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies.

Method: Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like Receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and Other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal Pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons.

Results: Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated Pyroptosis in hippocampal HT22 neurons.

Conclusion: Oridonin exerts neuroprotective effects by inhibiting Pyroptosis through the NLRP3/Caspase-1 pathway in chronic epilepsy model mice. It also reduces Pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy.

Keywords

Anticonvulsant profile; Epilepsy; NLRP3 inflammasome; Oridonin; Pyroptosis.

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