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

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.

Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

“…In a previous report [ 26 ], we demonstrated that resveratrol is a PGC-1α activator, and it can activate PGC-1α and the following signaling pathways and then promote mitochondrial biogenesis. To determine the causality of PGC-1α in modulation of VEGF on this experimental paradigm, we tested the effects of resveratrol, as a positive control, and siRNA against pgc-1α, as a negative control, on VEGF expression in the hippocampus following status epilepticus.…”

“…Following status epilepticus, the mechanism of endogenous neuronal survival signals is evolutionarily conserved and may actuate extensive signaling pathways to offer the neuroprotective effect which therefore may be strong candidates for therapeutic strategies [ 39 , 42 ]. In our previous studies, both in human epilepsy [ 43 ] and animal studies following status epilepticus [ 5 , 26 , 41 , 44 , 45 , 46 ], several endogenous neuroprotective mechanisms to lessen neuronal damage were proposed, including PPARγ [ 41 ], mitochondrial uncoupling protein 2 (UCP2) [ 41 ], heat shock protein 70 [ 43 , 44 ], brain-derived neurotrophic factor [ 45 ], mitochondrial dynamin-related protein 1 [ 46 ], PGC1-α [ 5 , 26 ], and sirtuin 1 [ 5 , 26 ].…”

“…In epileptic seizures, such as status epilepticus, the literature on the neuroprotective role of the VEGF-A/VEGFR2 pathway is limited. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC1-α) belongs to a small family of transcriptional coactivators identified as a cofactor for the nuclear hormone receptor PPARγ that possesses a common function in mitochondrial physiology and mitochondrial biogenesis [ 5 , 26 ]. Additionally, it is also involved in other metabolic processes, such as redox homeostasis, uncoupled respiration, and gluconeogenesis [ 26 , 27 , 28 ].…”

“…Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC1-α) belongs to a small family of transcriptional coactivators identified as a cofactor for the nuclear hormone receptor PPARγ that possesses a common function in mitochondrial physiology and mitochondrial biogenesis [ 5 , 26 ]. Additionally, it is also involved in other metabolic processes, such as redox homeostasis, uncoupled respiration, and gluconeogenesis [ 26 , 27 , 28 ]. Hypoxia-induced upregulation of VEGF mRNA is associated with increases in the transcription factor hypoxia inducible factor (HIF)1-α, which is also upregulated after cerebral ischemia [ 11 , 18 ].…”

DNA Methylation Changes are Associated with the Programming of White Adipose Tissue Browning Features by Resveratrol and Nicotinamide Riboside Neonatal Supplementations in Mice

“…Importantly, Slc27a1 and Prdm16 are both putative target genes of NRF1 according to ChIP-seq results in the ENCODE Transcription Factor Targets data set [49,50]. Moreover, RSV [51][52][53] and NR [54] both have been shown to induce NRF1 expression in experimental models as part of their stimulatory effects on mitochondrogenesis mediated by the activation of the SIRT1-PGC1α axis. Altogether, it is suggested that NRF1 may play a role in linking the observed effects of the neonatal treatments applied to methylation and transcription of both studied genes.…”