2. Academic Validation
  3. Huperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission

Huperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission

  • Acta Pharmacol Sin. 2025 Aug;46(8):2151-2162. doi: 10.1038/s41401-025-01522-w.
Yu Wang # 1,  Ke-Yu Hu # 1,  Qing-Yang Zhang # 1,  Ying-Jie Song # 1,  Ling-Jie Li 1,  Fei Wang 1,  Gang Tian 1,  Fan Fei 1 2,  Ceng-Lin Xu 1,  Jia-Jia Fang 2,  Xu-Hong Jiang 1,  Jian-Nong Wu 1,  Wen-Lu Li 1,  Yi Wang 3 4,  Zhong Chen 5 6
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences & The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 2 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences & The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 3 Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences & The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, China. wang-yi@zju.edu.cn.
  • 4 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences & The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China. wang-yi@zju.edu.cn.
  • 5 Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences & The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, China. chenzhong@zju.edu.cn.
  • 6 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences & The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China. chenzhong@zju.edu.cn.
  • # Contributed equally.
PMID: 40140526 DOI: 10.1038/s41401-025-01522-w
Abstract

Cholinergic transmission, independent of classical glutamatergic and GABAergic signaling, critically plays a crucial role in epilepsy. Huperzine A (Hup A), an acetylcholinesterase (AChE) inhibitor, exerts potent anticonvulsant activity, but its mechanism of action within cholinergic circuits remains unclear. Here, we show that Hup A mitigates epileptic seizures by enhancing hippocampal dorsal CA1 (dCA1)-projecting cholinergic transmission. We found that systemic injection of Hup A not only reduces seizures in acute models, including the maximal-electroshock seizure (MES), pentylenetetrazol (PTZ), and kainic acid (KA) models but also alleviates the seizure severity in chronic epilepsy models induced by kindling and KA, indicating a broad-spectrum anti-seizure efficacy. Interestingly, using immunohistochemistry, viral tracing, and in vivo fiber photometry, we found that Hup A selectively inhibits AChE in the dCA1 rather than in Other hippocampal subregions or cortex, enhancing dCA1-projecting septal cholinergic transmission. Significantly, selective ablation of septal ChAT+ neurons reversed the anti-seizure effects of Hup A. We further identified that α7 nicotinic acetylcholine receptors in the dCA1 region mediate the anti-seizures cholinergic circuit modulated by Hup A. Together, our results demonstrate that Hup A exerts broad-spectrum anti-seizure efficacy via modulating dCA1-projecting septal cholinergic transmission, providing potential therapeutic avenues for epilepsy through targeted cholinergic modulation.

Keywords

cholinergic circuit; epilepsy; hippocampal dorsal CA1 region; huperzine A; α7 nicotinic acetylcholine receptor.

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