Abstracts

Status epilepticus (SE) is a serious neurological condition broadly defined as a continuous seizure lasting ≥ 5 minutes or multiple seizures without full recovery of consciousness between them. Uncontrolled SE often 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, is well known for its pathogenic role in oxidative and inflammatory processes that can aggravate various tissue injuries. However, its involvement in SE-triggered neuroinflammation and long-term sequelae remains elusive.

We first characterized the expression of 12/15-LOX (encoded by Alox15) along with several proinflammatory genes in the hippocampus following LPS-induced neuroinflammation in mice. We then assessed the effects of a selective 12/15-LOX inhibitor ML351 on these key inflammatory mediators in LPS-activated primary microglial cultures and in the hippocampus of mice treated by LPS. Using a mouse pilocarpine model of SE, we evaluated the acute effects of ML351 on proinflammatory cytokines, neuronal death, and reactive gliosis in the hippocampus 24 h after SE onset. Finally, the long-term effects of ML351 on SE-provoked behavioral deficits were assessed using a battery of behavioral tests, including open field, light/dark preference, novel object recognition, and Y-maze.

Inhibition of 12/15-LOX by compound ML351 drastically reduced LPS-provoked proinflammatory gene expression both in vitro and in vivo. Treatment with ML351 (50 mg/kg, i.p.) after SE was interrupted by diazepam (10 mg/kg, i.p.) markedly decreased proinflammatory cytokines and reactive gliosis in the hippocampus and widely prevented neuronal injuries in the hippocampal regions CA1, CA3, and dentate hilus. These acute therapeutic benefits by ML351 were followed by a long-term improvement in spatial working and reference memory along with a reduction in anxiety-like behavior, measured 4 weeks after SE.

These new findings suggest that 12/15-LOX inhibition, even when administered two hours after SE onset, can alleviate neuroinflammation, protect hippocampal neurons, and prevent long-term behavioral deficits. Therefore, targeting 12/15-LOX might provide an adjunctive strategy, together with the current anti-seizure medications (ASMs), to mitigate neurobehavioral comorbidities associated with prolonged seizures.