Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1/NRF2 signaling pathways

Abstract Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2–related factor 2 (NRF2) and silencing information regulator 1 ( Sirt1 ) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.