Status epilepticus-induced 12/15-lipoxygenase drives neuroinflammation and contributes to neuronal injuries and behavioral comorbidities

Status epilepticus (SE) is a serious neurological condition defined as a continuous seizure lasting longer than 5 min or multiple seizures without full recovery of consciousness between them. Uncontrolled SE causes severe brain inflammation and damage, leading to life-long epilepsy and behavioral comorbidities. 12/15-Lipoxygenase (12/15-LOX), an enzyme that generates bioactive lipid metabolites from polyunsaturated fatty acids, plays pathogenic role in oxidative and inflammatory processes that can aggravate tissue injuries. However, its involvement in SE-triggered neuroinflammation and long-term sequelae remains elusive. Herein, we report that 12/15-LOX was significantly upregulated in microglia in response to inflammatory stimuli as well as in the hippocampus after pilocarpine-induced SE in mice. Selective inhibition of 12/15-LOX by compound ML351 robustly reduced lipopolysaccharide-provoked pro-inflammatory gene expression both in vitro and in vivo. Treatment with ML351 (50 mg/kg, i.p.) after SE was interrupted by diazepam markedly decreased pro-inflammatory cytokines and reactive gliosis and broadly prevented neuronal injuries within the hippocampus. Moreover, repeated administration of ML351 for merely five consecutive days after SE led to a long-term improvement in spatial working and reference memory along with a reduction in anxiety-like behavior as well as an increase in hippocampal neuronal survival. These results suggest that inhibition of 12/15-LOX hours after SE onset can alleviate neuroinflammation, protect hippocampal neurons, and prevent long-term neurobehavioral deficits. Therefore, targeting 12/15-LOX might provide an adjunctive strategy, together with the current antiseizure medications, to mitigate neurobehavioral comorbidities associated with prolonged seizures.