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

Neuropharmacology. 2020 Jan 1;162:107760. doi: 10.1016/j.neuropharm.2019.107760. Epub 2019 Sep 4.

Abstract

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 α-asaronol, a metabolic product of α-asarone, on pentylenetetrazole (PTZ)-induced seizures in zebrafish and investigated the underlying mechanisms. As a result, α-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 α-asaronol pretreated zebrafish, we found that α-asaronol attenuate seizures through increase of PPAR γ expression, while PPAR γ antagonist GW9662 inhibit the anti-seizures actions of α-asaronol. Moreover, molecular docking simulation implied the physical interaction between α-asaronol and PPAR γ. The overall results indicated that the anticonvulsant effects of α-asaronol are regulated through PPAR γ-mediated pathway, which shed light on development of α-asaronol as a potential antiepileptic drug. In addition, it is for first time to report that PPAR γ is associated with seizures in zebrafish, supporting previous evidence that zebrafish is a suitable alternative for studying seizures.

Keywords: GW9662; PPAR γ; Seizures; Zebrafish; α-asaronol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allylbenzene Derivatives
  • Anilides / pharmacology*
  • Animals
  • Anisoles / pharmacology*
  • Anticonvulsants / pharmacology*
  • Behavior, Animal / drug effects
  • Convulsants
  • Hydroxides / pharmacology
  • Locomotion / drug effects*
  • Molecular Docking Simulation
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / drug effects*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Pentylenetetrazole
  • RNA-Seq
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Seizures / genetics*
  • Seizures / metabolism
  • Transcriptome
  • Zebrafish

Substances

  • 2-chloro-5-nitrobenzanilide
  • Allylbenzene Derivatives
  • Anilides
  • Anisoles
  • Anticonvulsants
  • Convulsants
  • Hydroxides
  • PPAR gamma
  • alpha-asaronol
  • asarone
  • Pentylenetetrazole