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(+)-Borneol Enhances the Antiseizure Effects of Retigabine by both Pharmacokinetic and Pharmacodynamic Interaction

文献类型：期刊论文

作者Xu, Haiyan2; Wu, Zhidan1,3; Wang, Pei2; Gong, Jili1; Qiu, Li1; Gu, Yueling2; Zhan, Li2; Tian, Fuyun1; Gao, Zhaobing1,2,3
刊名NEUROCHEMICAL RESEARCH
出版日期2025-06-01
卷号50期号:3页码:13
关键词Epilepsy Retigabine (+)-Borneol Synergistic interaction KCNQ channels
ISSN号0364-3190
DOI10.1007/s11064-025-04396-w
英文摘要Epilepsy is a chronic neurological disorder characterized by recurrent seizures, approximately one-third of whom are resistant to current anti-seizure drugs (ASDs). Retigabine (RTG) is a potential treatment for treating drug-resistant epilepsy and KCNQ2-related developmental and epileptic encephalopathy (KCNQ2-DEE). However, its use is limited by side effects from high doses and long-term use. This study aims to evaluate the anticonvulsant efficacy of RTG in combination with (+)-borneol in mouse models of maximal electroshock seizure (MES) and 6-Hz (44-mA) seizure. The individual anti-seizure efficacy of RTG and (+)-borneol was evaluated in the MES and 6-Hz seizure models, then isobolographic analysis was conducted to assess their interactions. The plasma and brain concentrations of RTG were measured with and without (+)-borneol. Electrophysiological experiments using the patch-clamp technique investigated the interactions of (+)-borneol and RTG at the alpha 1 beta 3 gamma 2L-GABAAR and KCNQ2 channels. Both RTG and (+)-borneol exhibited anticonvulsant activity in MES and 6-Hz seizure models. In the isobolographic analysis, the co-administration of RTG and (+)-borneol proved to be significantly more effective than predicted based on additive effects. The ED50mix was reduced by approximately 20 to 100-fold and 2 to 6-fold compared to the ED50add in the MES and 6-Hz models, respectively. The plasma and brain levels of RTG increased following co-administration with higher doses of (+)-borneol. Patch-clamp studies indicated that both RTG and (+)-borneol positively modulated alpha 1 beta 3 gamma 2L-GABAAR currents and showed additive effects. However, (+)-borneol inhibited the KCNQ2 current at 100 mu M and did not enhance RTG activation on KCNQ2 channels at this concentration. These results demonstrate that (+)-borneol enhances the antiseizure effects of RTG by both pharmacokinetic and pharmacodynamic interaction and this approach may be clinically effective for patients with intractable seizures or KCNQ2-DEE.
WOS关键词BLOOD-BRAIN-BARRIER ; COMBINATION THERAPY ; POTASSIUM CHANNELS ; BORNEOL ; EZOGABINE ; EPILEPSY ; DISCOVERY ; EDARAVONE
资助项目Guangdong Basic and Applied Basic Research Foundation ; High-level New RD Institute[2019B090904008] ; High-level Innovative Research Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province[2021ZD0200900] ; Zhongshan Municipal Bureau of Science and Technology[CXTD2022013] ; Zhongshan Municipal Natural Science Foundation[221018194369472] ; [2023A1515110516]
WOS研究方向Biochemistry & Molecular Biology ; Neurosciences & Neurology
语种英语
WOS记录号WOS:001470002000002
出版者SPRINGER/PLENUM PUBLISHERS
源URL[http://119.78.100.183/handle/2S10ELR8/317485]  
专题新药研究国家重点实验室
通讯作者Tian, Fuyun; Gao, Zhaobing
作者单位1.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Haiyan,Wu, Zhidan,Wang, Pei,et al. (+)-Borneol Enhances the Antiseizure Effects of Retigabine by both Pharmacokinetic and Pharmacodynamic Interaction[J]. NEUROCHEMICAL RESEARCH,2025,50(3):13.
APA Xu, Haiyan.,Wu, Zhidan.,Wang, Pei.,Gong, Jili.,Qiu, Li.,...&Gao, Zhaobing.(2025).(+)-Borneol Enhances the Antiseizure Effects of Retigabine by both Pharmacokinetic and Pharmacodynamic Interaction.NEUROCHEMICAL RESEARCH,50(3),13.
MLA Xu, Haiyan,et al."(+)-Borneol Enhances the Antiseizure Effects of Retigabine by both Pharmacokinetic and Pharmacodynamic Interaction".NEUROCHEMICAL RESEARCH 50.3(2025):13.

入库方式： OAI收割

来源：上海药物研究所

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