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(+)-Borneol enantiomer ameliorates epileptic seizure via decreasing the excitability of glutamatergic transmission

Acta Pharmacologica Sinica volume 44, pages 1600–1611 (2023)Cite this article

Abstract

Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 μM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.

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Fig. 1: (+)-Borneol dose-dependently attenuates acute epileptic seizure in MES- and PTZ-induced models.
Fig. 2: (+)-Borneol attenuates epileptic seizures in the hippocampal-kindling model.
Fig. 3: (+)-Borneol enantiomers show broad-spectrum and optimal anti-seizure effects.
Fig. 4: (+)-Borneol attenuates spontaneous seizures in the KA-induced chronic epilepsy model.
Fig. 5: (+)-Borneol decreases the excitability of glutamatergic transmission.
Fig. 6: (+)-Borneol decreases the enhanced glutamatergic transmission in epileptic mice.

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Acknowledgements

This project was supported by grants from the National Key R&D Program of China (2021ZD0202803 and 2020YFA0803902), the National Natural Science Foundation of China (82022071), the Natural Science Foundation of Zhejiang Province (LD22H310003) and the Research Project of Zhejiang Chinese Medical University (2022JKJNTZ13).

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  1. These authors contributed equally: Yu Wang, Xiao-yun Qiu, Jia-ying Liu

Authors and Affiliations

  1. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Department of Neurology, The First Affiliated Hospital, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Yu Wang, Xiao-yun Qiu, Jia-ying Liu, Bei Tan, Fei Wang, Min-juan Sun, Xu-hong Jiang, Xu-ming Ji, Ceng-lin Xu, Yi Wang & Zhong Chen

  2. Zhejiang Rehabilitation Medical Center, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310061, China

    Yi Wang

  3. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310012, China

    Yi Wang & Zhong Chen

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Contributions

ZC, YiW, and YuW designed the research. YuW, XYQ, JYL, FW, and MJS conducted the experiments. YuW, XYQ, and YiW conducted the data analysis. BT, XHJ, XMJ, and CLX provided technical guidance and contributed to the data discussion. YuW and YiW wrote the paper. YiW 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., Qiu, Xy., Liu, Jy. et al. (+)-Borneol enantiomer ameliorates epileptic seizure via decreasing the excitability of glutamatergic transmission. Acta Pharmacol Sin 44, 1600–1611 (2023). https://doi.org/10.1038/s41401-023-01075-w

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