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

IF 3.8 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemical Research Pub Date : 2025-04-19 DOI:10.1007/s11064-025-04396-w

Haiyan Xu, Zhidan Wu, Pei Wang, Jili Gong, Li Qiu, Yueling Gu, Li Zhan, Fuyun Tian, Zhaobing Gao

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Abstract

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 α1β3γ2L-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 α1β3γ2L-GABAAR currents and showed additive effects. However, (+)-borneol inhibited the KCNQ2 current at 100 µM 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.

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（+）-冰片通过药代动力学和药效学相互作用增强雷加滨的抗癫痫作用

癫痫是一种以反复发作为特征的慢性神经系统疾病，其中约三分之一的患者对目前的抗癫痫药物（asd）具有耐药性。雷沙滨（RTG）是治疗耐药癫痫和kcnq2相关的发育性和癫痫性脑病（KCNQ2-DEE）的潜在治疗方法。然而，它的使用受到高剂量和长期使用的副作用的限制。本研究旨在评价RTG联合(+)-冰片在最大电休克发作（MES）和6 hz （44 ma）发作小鼠模型中的抗惊厥作用。在MES和6 hz癫痫发作模型中，分别评价RTG和(+)-冰片的抗癫痫效果，并进行等尺度分析以评估它们的相互作用。分别用(+)-冰片和不加冰片测定RTG的血浆和脑浓度。采用膜片钳技术的电生理实验研究了(+)-冰片与RTG在α1β3γ2L-GABAAR和KCNQ2通道上的相互作用。RTG和(+)-冰片在MES和6hz癫痫发作模型中均表现出抗惊厥活性。在等温分析中，RTG和(+)-冰片的联合使用被证明比基于加性效应的预测更有效。与MES和6 hz型号的ED50add相比，ED50mix分别减少了约20至100倍和2至6倍。与高剂量的(+)-冰片共同给药后，血浆和脑内RTG水平升高。膜片钳研究表明，RTG和(+)-冰片均能正向调节α1β3γ2L-GABAAR电流，并表现出加性效应。然而，(+)-冰片在100µM时抑制KCNQ2电流，并没有增强该浓度下KCNQ2通道上的RTG激活。这些结果表明(+)-冰片通过药代动力学和药效学相互作用增强RTG的抗癫痫作用，这种方法可能对难治性癫痫或KCNQ2-DEE患者有效。

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来源期刊

Neurochemical Research 医学-神经科学

CiteScore

7.70

自引率

2.30%

发文量

320

审稿时长

6 months

期刊介绍： Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.