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

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.