Inhibition of aerobic glycolysis suppresses ferroptosis via activation of the AMPK-FoxO3a pathway in epileptic rats.

Abstract

BACKGROUND: Ferroptosis has recently been implicated in seizure-induced neurodegeneration, whereas enhanced aerobic glycolysis during seizures may aggravate oxidative stress and ferroptotic damage. This study investigated whether inhibition of aerobic glycolysis suppresses ferroptosis through activation of the AMP-activated protein kinase (AMPK)-Forkhead box O3a (FoxO3a) signaling pathway in epileptic rats. METHODS AND RESULTS: A pilocarpine (PILO)-induced epilepsy model was established in male Wistar rats. Animals were treated with the aerobic glycolysis inhibitor 2-deoxy-D-glucose (2-DG), with or without the AMPK inhibitor Compound C. Behavioral evaluation, Morris water maze testing, biochemical assays, immunohistochemistry, quantitative real-time PCR, western blotting, and mitochondrial membrane potential analyses were performed. Epileptic rats exhibited significant upregulation of pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1), and lactate dehydrogenase A (LDHA), indicating enhanced aerobic glycolysis in the hippocampus. Treatment with 2-DG significantly reduced seizure severity and improved spatial learning and memory. Moreover, inhibition of aerobic glycolysis markedly decreased Fe²⁺ and malondialdehyde (MDA) accumulation, restored glutathione (GSH) and glutathione peroxidase 4 (Gpx4) levels, preserved mitochondrial membrane potential, and enhanced AMPK and FoxO3a activation. These protective effects were substantially reversed by Compound C administration. CONCLUSION: Inhibition of aerobic glycolysis attenuates seizure-induced ferroptosis through activation of the AMPK-FoxO3a pathway. These findings establish a mechanistic link between metabolic reprogramming and ferroptosis in epilepsy and suggest that targeting aerobic glycolysis may represent a promising therapeutic strategy for neuroprotection in epilepsy.