3-Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging.

Abstract

In the present study, attempts have been made to evaluate the potential role of 3 Bromopyruvate (3-BP) a glycolytic inhibitor and a caloric restriction mimetic (CRM), to exert neuroprotection in rats during aging through modulation of autophagy. Young male rats (4 months), and naturally aged (22 months) male rats were supplemented with 3-BP (30mg/kg b.w., orally) for 28 days. Our results demonstrate a significant increase in the antioxidant biomarkers (ferric reducing antioxidant potential level, total thiol, superoxide dismutase, and catalase activities) and a decrease in the level of pro-oxidant biomarkers such as protein carbonyl after 3-BP supplementation in brain tissues. A significant increase in reactive oxygen species (ROS) was observed due to the mitohormetic effect of 3-BP supplementation in the treated rats. Furthermore, the 3-BP treatment also enhanced the activities of electron transport chain complexes I and IV in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuroprotective and aging marker genes. RT-PCR data revealed that 3-BP up-regulated the expression of autophagy markers genes (Beclin-1 and LC3 β), sirtuin-1, and neuronal marker gene (NSE), respectively in the aging brain. The results suggest that 3-BP induces a mitohormetic effect through the elevation of ROS which reinforces defensive mechanism(s) targeted at regulating autophagy. These findings suggest that consistently low-dose 3-BP may be beneficial for neuroprotection during aging and age-related disorders.