Metabolic and redox modulation by 2-deoxy-D-glucose and sodium selenite protects against pentylenetetrazole-kindled seizures, neuroinflammation and cognitive dysfunction.

Cellular metabolism, disrupted brain bioenergetics adaptability and neuroinflammation are inextricably linked in epileptogenesis. Their pathological interplay exacerbates glutamatergic storming, free-radical induced excitotoxicity and glial reactivity leading to network hyperexcitability. Therefore, a novel metabolic approach concurrently targeting cerebral energy metabolism, oxidative stress and neuroinflammation represents a rationale approach for dual seizure control and neuroprotection. 2-deoxy-D-glucose (2DG) inhibits glycolysis while sodium selenite (NaSe) mediates potent anti-inflammatory and anti-oxidant effects. We assumed that the combined intervention would efficiently halt kindling, electroencephalographic ictal activity and associated progression of behavioral comorbidities in PTZ-induced murine model of epilepsy. Furthermore we also evaluated impact of 2DG+NaSe combination on neuroinflammatory markers, oxidative stress markers and histopathological changes in CA1, CA3 and DG subregions of cornu ammonis. Our results demonstrated that combination significantly reduced seizure scores with normalization of aberrant cortical epileptiform discharges and associated quantitative parameters (spike counts, average cyclic height and spiking frequency). This dual approach markedly halted PTZ-induced anxiety-like phenotype and cognitive decline as all animals showed good performance in relevant neurobehavioral assays (OFT, L/D, HBT, T-maze, NOR, and MWM). Mechanistically, combination might have altered glial reactivity and pro-inflammatory cytokines as evidenced by reduced mRNA expression levels of GFAP, IL-1β, and TNF-ɑ. In addition it prompts redox homeostasis (↑ SOD, CAT and GPx enzymatic activity and ↓ MDA levels) and preserved histoarchitecture across cornu ammonis subfields. These outcomes reinforces that concurrent metabolic and oxidative pathways targeting confers robust management of seizure burden and neuroprotection, positioning this combination as a potential multi-modal intervention for patients with DRE.