Involvement of peroxisome proliferator-activated receptor gamma in anticonvulsant activity of alpha-asaronol against pentylenetetrazole-induced seizures in zebrafish

摘要

In mammals, peroxisome proliferators activated receptors (PPARs), the nuclear hormone receptors, have been reported to be involved in seizure control. Selective agonists and antagonists of PPARs raise seizure thresholds and suppress seizures, respectively. In this study, we evaluated the anticonvulsant effects of alpha-asaronol, a metabolic product of a-asarone, on pentylenetetrazole (PTZ)-induced seizures in zebrafish and investigated the underlying mechanisms. As a result, alpha-asaronol ameliorated seizures with increase of seizure latency, as well as decrease of seizure-like behavior, c-fos expression, and abnormal neuronal discharge in a concentration dependent manner. By comparing gene expression profiles of zebrafish undergoing seizures and alpha-asaronol pretreated zebrafish, we found that alpha-asaronol attenuate seizures through increase of PPAR gamma expression, while PPAR gamma antagonist GW9662 inhibit the anti-seizures actions of alpha-asaronol. Moreover, molecular docking simulation implied the physical interaction between alpha-asaronol and PPAR gamma. The overall results indicated that the anticonvulsant effects of alpha-asaronol are regulated through PPAR gamma-mediated pathway, which shed light on development of alpha-asaronol as a potential antiepileptic drug. In addition, it is for first time to report that PPAR gamma is associated with seizures in zebrafish, supporting previous evidence that zebrafish is a suitable alternative for studying seizures.