Abstract WP154: The Role of Ethylmethylhydroxypyridine Succinate in the Induction of PGC-1α in Experimental Ischemic Damage of the Prefrontal Cortex

Abstract

The aim of the study was to identify the potential succinate/SUCNR1-mediated mechanism of induction and activation of transcription coactivator PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha) – key activator of the mitochondriogenesis, angiogenesis, fusion of mitochondria, antioxidant defense system that are basis of neuroprotective mechanisms – in the peri-infarction zone of the rat prefrontal cortex (PFC). Focal bilateral damage of the PFC was modeled by photo-induced thrombosis. Ethylmethylhydroxypyridine succinate (a form of succinate passing through the blood-brain barrier; trade name of the drug Mexidol) was injected intraperitoneally 2 hours after infarction and then every day at a dose of 100 mg/kg (7 day course). The tissue of the peri-infarction zone was taken 1, 3, 7 days after the start of therapy, as well as 14 days after discontinuation of the drug. Brain samples were stored in liquid nitrogen, a cytosolic extract was obtained, expression levels of SUCNR1, PGC-1α, transcription factors (NRF1, TFAM), VEGF, catalytic subunits of mitochondrial respiratory enzymes (NDUFV2, SDHA, cyt c1, COX2) and ATP synthases (ATP5A) were determined by Western blot analysis. The study showed that the content of PGC-1α in the peri-infarct zone decreased one day after the induction of ischemic damage by 40% and remained reduced for 21 days after a ischemia. The course of injection of mexidol stabilized PGC-1α in the peri-ischemic zone at a level comparable to the control, both at the stage of treatment and drug withdrawal, and in intact rats induced PGC-1α by 30%. Induction of NRF1, TFAM, NDUFV2, SDHA, cyt c1, ATP5A, indicating the activation of PGC-1α, was observed in rats of the three compared groups, however, the highest expression levels were found in animals subjected to the course of mexidol. Also it was revealed overexpression of SUCNR1 and VEGF in ischemic and intact rats, were injected with mexidol. The study demonstrates for the first time that succinate/SUCNR1 signaling is involved not only in the mechanisms of cerebral angiogenesis, but also in the mechanisms of PGC-1α-dependent neuroprotection. The study opens up new perspectives for pharmacological modulation of PGC-1α levels in the ischemic brain.