Perampanel Stimulates Mitochondrial Biogenesis in Neuronal Cells through Activation of the SIRT1/PGC-1α Signaling Pathway.

Mitochondrial biogenesis plays an important role in maintaining mitochondrial integrity in the central nervous system. Perampanel is an antiepilepsy reagent, which has been recently reported to exert neuroprotective effects. In the present study, we aim to investigate the protective effects of perampanel on mitochondrial biogenesis and mitochondrial bioenergetics in human neuronal cells. The human SH-SY-5Y neuronal cells were incubated with 1 and 2 μM perampanel for 24 h. The ratio of mtDNA to nDNA (mtDNA/nDNA) and the gene expression levels of Tomm20, Timm50, Atp5c1, and complex I subunit NDUFB8 were determined using real-time PCR and the Western blot analysis. Spare respiratory capacity was indicated using maximum oxygen consumption rates (OCRs) calculated as a percentage of baseline OCR and ATP concentrations, which were determined using a luciferin/luciferase ATP bioluminescence kit. The siRNA against PGC-1α was designed and transfected to knock down the expression of PGC-1α. Our results indicate that perampanel stimulated mitochondrial biogenesis by increasing mtDNA/nDNA, gene expressions of Tomm20, Timm50, Atp5c1, and the protein level of the complex I subunit NDUFB8. Additionally, perampanel improved mitochondrial bioenergetics by increasing spare respiratory capacity and ATP production. Importantly, perampanel increased the expressions of PGC-1α, NRF1, TFAM, and SIRT1. Importantly, the effects of perampanel in mitochondrial biogenesis were abolished by the knockdown of PGC-1α or blockage of SIRT1 with its specific inhibitor EX-527. These findings suggest that perampanel might improve mitochondrial biogenesis in neuronal cells by activating the SIRT1/PGC-1α signaling pathway.