Modulation of the HMGB1/TLR4 pathway by montelukast in PTZ-induced epilepsy: alleviating neuroinflammatory oxidative stress and seizure severity

Epilepsy is a multifactorial neurological disorder often associated with neuroinflammatory processes that contribute to the persistence of recurrent seizures. Conventional antiepileptic drugs (AEDs) frequently fail to achieve complete seizure control, highlighting the urgent need for alternative therapeutic strategies. Recent studies have explored the potential of montelukast, a leukotriene receptor antagonist, in the management of neurological disorders, including epilepsy. : In the present study, the neuroprotective and antiepileptic effects of montelukast were evaluated using a pentylenetetrazol (PTZ)-induced kindling model in mice. A total of six groups were established, each consisting of nine mice, and animals were randomly assigned to the groups. PTZ (25 mg/kg, i.p.) was administered on alternate days for six weeks to induce kindling. Montelukast (MTK) was tested at three dose levels (5, 10, and 20 mg/kg, i.p.), while levetiracetam (30 mg/kg, i.p.) served as the standard comparator. : Montelukast (20 mg/kg) significantly reduced seizure severity, as indicated by lower Racine scale scores, and improved cognitive performance in both the elevated plus maze and passive avoidance tests. Biochemical analyses demonstrated increased catalase activity, reduced glutamate levels, and elevated γ-aminobutyric acid (GABA) concentrations. Furthermore, montelukast significantly decreased pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as other mediators of neuroinflammation such as high-mobility group box-1 (HMGB1), transforming growth factor-β (TGF-β), matrix metalloproteinase-9 (MMP-9), and toll-like receptor-4 (TLR-4). Histopathological findings confirmed that montelukast administration preserved cortical and hippocampal integrity by reducing neuronal damage. : Collectively, these findings indicate that montelukast exhibits significant anticonvulsant and neuroprotective effects in a PTZ-induced epilepsy model, supporting its potential as a therapeutic candidate for epilepsy and warranting further investigation.