Protective Effect of Resveratrol on the Brain in a Rat Model of Epilepsy

Abstract

Accumulating evidence has suggested resveratrol as a promising drug candidate for the treatment of epilepsy. To validate this, we tested the protective effect of resveratrol on a kainic acid (KA)-induced epilepsy model in rats and investigated the underlying mechanism. We found that acute resveratrol application partially inhibited evoked epileptiform discharges in the hippocampal CA1 region. During acute, silent and chronic phases of epilepsy, the expression of hippocampal kainate glutamate receptor (GluK2) and the GABA_A receptor alpha1 subunit (GABA_AR-alpha1) was up-regulated and down-regulated, respectively. Resveratrol reversed these effects and induced an antiepileptic effect. Furthermore, in the chronic phase, resveratrol treatment inhibited the KA-induced increased glutamate/GABA ratio in the hippocampus. The antiepileptic effects of resveratrol may be partially attributed to the reduction of glutamate-induced excitotoxicity and the enhancement in GABAergic inhibition.

Keywords: Epilepsy; GABA; Glutamate; Hippocampus; Resveratrol.

Fig. 1

Resveratrol has no effect on the amplitude of population spikes in the control group. A A single PS in the hippocampal CA1 pyramidal cell layer of a control rat (arrow, stimulus artifact). B Acute application of resveratrol (5, 15, and 50 μmol/L) to hippocampal slices from the control group did not alter the PS amplitude (8 slices from 3 rats, P >0.05).

Fig. 2

Epileptiform discharges are evoked in the hippocampal CA1 region of rat models of TLE induced by KA. A Typical multiple peaks of PS epileptiform discharges recorded in a hippocampal slice from a rat with KA-induced TLE. B After acute perfusion with resveratrol (Res; 5 μmol/L) for 20 min, the amplitudes of the first 4 PS peaks and the total number of PS peaks were not affected (6 slices from 4 rats, P >0.05). C The amplitudes of the first 4 PS peaks and the total number of PS peaks were not affected by perfusion with 15 μmol/L Res for 20 min (6 slices from 4 rats, P >0.05). D After perfusion with 50 μmol/L Res for 20 min, the amplitudes of the first 4 PS peaks were clearly decreased (6 slices from 5 rats, **P <0.01). E When slices from the control group were perfused with 50 μmol/L Res for 20 min, the amplitudes of the PS peaks were clearly decreased (6 slices from 5 rats, **P <0.01).

Fig. 3

Epileptiform discharges are evoked by bicuculline (Bic) in the rat hippocampal CA1 region. A A repetitive pattern of PS epileptiform discharges induced by perfusing Bic (30 μmol/L) for 20 min onto hippocampal slices from the control group. B, C Acute exposure to 5 μmol/L or 15 μmol/L resveratrol (Res) for 20 min in the slices from the control group did not affect the amplitudes of the first 4 PS peaks and the total number of PS peaks (6 slices from 5 rats, P >0.05). D After perfusion with 50 μmol/L Res for 20 min, the amplitudes of the first 4 PS peaks were clearly decreased (8 slices from 5 rats, **P <0.01). E The 20-min application of 50 μmol/L Res induced a decrease in the total number of PS peaks and recovered quickly after washout (8 slices from 5 rats, **P <0.01).

Fig. 4

Effects of resveratrol (Res) on the expression of Glu-6 and GABA_A receptor-α1 in different phases of epilepsy with Western blot analysis. A Representative western blots showing that Res modulated the expression of GluR6 in the hippocampus in the acute, silent, and chronic phases. B Densitometric analysis showing that GluR6 expression was reduced in the acute phase, barely detectable in the silent phase, and markedly increased in the chronic phase in the KA group. Resveratrol treatment up-regulated GluR6 expression in the acute and silent phases, but down-regulated it in the chronic phase. C Western blotting analysis of the effects of Res on the expression of GABAR-α1 in the hippocampus in the acute, silent, and chronic phases. D Densitometric analysis showing that GABA_AR-α1 expression was significantly reduced in the acute phase, barely detectable in the silent phase, and markedly increased in the chronic phase in the KA group. Res treatment up-regulated GABA_AR-α1 expression in the acute, silent, and chronic phases. *P <0.05, **P <0.01 vs control group; ^# P <0.05, ^## P <0.01 vs KA group (n = 8).