Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway.

Yao-Chung Chuang,Shuo-Bin Jou,Shu-Fang Chen,Chung-Yao Hsu,Nai-Ching Chen,Shang-Der Chen

doi:10.3390/ijms20040998

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.

Highlights

Status epilepticus, or the condition of continuous epileptic seizures, is a major neurological and medical emergency that is associated with significant morbidity and mortality [1]
With a clinically related animal model of status epilepticus, the present study shows changes of mitochondrial biogenesis machinery induced by sustained epileptic seizures that upregulated PGC-1α expression, and resveratrol, the activator of PGC-1α, was accompanied by increased PGC-1α expression and promotion of mitochondrial biogenesis
The mitochondrial uncoupling protein 2 (UCP2) is known as an endogenous neuroprotective molecule in many neurological disorders [41,42]. With this status epilepticus model, we demonstrated that activation of peroxisome proliferator-activated receptor γ (PPARγ) increased mitochondrial UCP2 expression, decreased mitochondrial translocation of Bax, reduced cytosolic release of cytochrome c by stabilizing the mitochondrial transmembrane potential, and lessened apoptotic neuronal cell death in the hippocampus [43]

Summary

Introduction

The condition of continuous epileptic seizures, is a major neurological and medical emergency that is associated with significant morbidity and mortality [1]. In studies of both humans and animal models, results showed many changes and cascades of events at the cellular level, including activation of glutamate transmission, changes in the ingredient of γ-aminobutyric acid and glutamate receptors, activation of inflammatory cytokines, increased oxidative stress, mitochondrial dysfunction, activations of neuronal plasticity, and activation of late cell death pathways, which may play crucial roles in the development of brain damage and the decline of cognition [1,2,3,4]. Several studies, including ours, showed that seizure-affected mitochondrial fission expression with neuronal damage and alteration of mitochondrial dynamic protein expression can provide a protective effect opposing seizure-induced hippocampal neuronal damage [5,11,12]

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