ANTIEPILEPTOGENIC EFFECT OF CDDO-EA VIA DUAL MODULATION OF OXIDATIVE STRESS AND INFLAMMATION IN PRECLINICAL EPILEPSY MODELS

Epilepsy remains a major neurological disorder, with a substantial proportion of patients refractory to existing antiseizure therapies, highlighting the need for interventions that modify disease progression. Oxidative stress and neuroinflammation are key drivers of seizure generation and epileptogenesis, and modulation of these pathways via Nrf2 activators represents a promising therapeutic strategy. Here, we investigated the effects of CDDO-EA, a pharmacological Nrf2 activator, in preclinical models of epilepsy. Acute seizure protection was evaluated in the pentylenetetrazol (PTZ) model, and antiepileptogenic efficacy was assessed in the kainic acid-induced status epilepticus (KA-SE) model using chronic video-electrocorticographic recordings. In the PTZ model, CDDO-EA pretreatment reduced seizure incidence, delayed onset, attenuated severity, and decreased markers of oxidative stress (lipid peroxidation, catalase, and superoxide levels) and pro-inflammatory cytokines. In the KA-SE model, CDDO-EA significantly suppressed the emergence of spontaneous recurrent seizures, evidenced by lower seizure frequency, reduced cumulative seizure burden, and prolonged latency to first seizure. Treated animals also exhibited decreased hippocampal oxidative DNA damage and reduced expression of neuroinflammatory cytokines. These results indicate that CDDO-EA confers both acute seizure protection and long-term suppression of epileptogenesis, likely via Nrf2-dependent regulation of redox and inflammatory pathways. Collectively, our findings suggest that CDDO-EA may represent a promising therapeutic candidate for seizure control while also mitigating the progression of epileptogenesis.