Selective inhibition of NOX2 after status epilepticus attenuates epileptogenesis and cognitive impairment: A sex-dependent study

Epilepsy, a chronic neurological disorder affecting approximately 1 % of the global population, is characterized by recurrent seizures that are often refractory to current antiseizure medications (ASMs). These pharmacotherapies predominantly suppress symptoms without intervening in the underlying pathophysiological cascade, which includes persistent oxidative stress and neuroinflammation, key drivers of epileptogenesis and pharmacoresistance. Among the primary enzymatic sources of reactive oxygen species (ROS), NADPH oxidase 2 (NOX2) has emerged as a central mediator of redox imbalance and neuroimmune activation in the brain. However, the sex-specific roles of NOX2 and its modulation as a therapeutic strategy remain largely unexplored. Here, we investigated the therapeutic efficacy of GSK2795039, a selective and functionally active NOX2 inhibitor, in a kainic acid (KA)-induced status epilepticus (SE) rat model. We examined both acute and chronic outcomes of early NOX2 inhibition on oxidative stress, neuroinflammation, hippocampal neurodegeneration, and cognitive function, incorporating rigorous analysis of sex-dependent responses. Long-term effects on epileptogenesis were assessed using continuous 24/7 video-electrocorticographic (vECoG) monitoring. Our results revealed that early GSK2795039 intervention significantly attenuated SE-induced oxidative damage, pro-inflammatory cytokine expression, and neuronal death, thereby mitigating the development of spontaneous recurrent seizures. Notably, male rats exhibited a more robust therapeutic response, including a marked reduction in seizure burden and improved cognitive performance, whereas females displayed a more modest response, suggesting the presence of compensatory or NOX2-independent antioxidant mechanisms. These findings underscore the pivotal role of NOX2-derived ROS in driving epileptogenesis and highlight the translational potential of NOX2-targeted therapies. Importantly, our study revealed a clear sex divergence in therapeutic outcomes, reinforcing the necessity of integrating sex as a critical biological variable in preclinical and clinical strategies aimed at disease modification in epilepsy.