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

Acta Pharmacologica Sinica volume 46, pages 2151–2162 (2025)Cite this article

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.

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Fig. 1: Hup A attenuates epileptic seizures in various acute seizure models.
Fig. 2: Hup A ameliorates the development of hippocampal seizures.
Fig. 3: Hup A relieves the chronic spontaneous seizures in KA-induced TLE.
Fig. 4: Hup A increases the MS-dCA1 cholinergic transmission.
Fig. 5: Hup A attenuates epileptic seizures by enhancing the MS-dCA1 cholinergic transmission.
Fig. 6: α7 nACh receptors mainly mediate anti-seizure cholinergic circuit modulated by Hup A.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgments

This project was supported by grants from the National Natural Science Foundation of China (82373859, 82330116, 82404590, and 82401698), the Natural Science Foundation of Zhejiang Province (LD24H310001 and LD22H310003), and the Postdoctoral Science Foundation of China (2023M743144).

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Author notes

  1. These authors contributed equally: Yu Wang, Ke-yu Hu, Qing-yang Zhang, Ying-jie Song.

Authors and Affiliations

  1. Zhejiang Key Laboratory of Neuropsychopharmacology, School of Pharmaceutical Sciences & The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yu Wang, Ke-yu Hu, Qing-yang Zhang, Ying-jie Song, Ling-jie Li, Fei Wang, Gang Tian, Fan Fei, Ceng-lin Xu, Xu-hong Jiang, Jian-nong Wu, Wen-lu Li, Yi Wang & Zhong Chen

  2. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences & The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Fan Fei, Jia-jia Fang, Yi Wang & Zhong Chen

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Contributions

The main idea of this study was from Yi W, ZC, and Yu W. Yu W, KYH, QYZ, YJS, LJL, and FW conducted the experiments. Yu W, KYH, and QYZ conducted the data analysis. GT, FF, CLX, JJF, XHJ, and JNW provided technical guidance and contributed to the data discussion. Yu W and Yi W wrote the manuscript. WLL and Yi W edited the manuscript. Yi W and ZC supervised all aspects of the work.

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Correspondence to Yi Wang or Zhong Chen.

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Wang, Y., Hu, Ky., Zhang, Qy. et al. Huperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission. Acta Pharmacol Sin 46, 2151–2162 (2025). https://doi.org/10.1038/s41401-025-01522-w

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