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, frequently associated with neuroinflammatory processes that contribute to the persistence of recurrent seizures. Conventional antiepileptic drugs (AEDs) often fail to achieve complete seizure control, thereby emphasizing the urgent need for alternative therapeutic approaches. Recent studies have examined 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 assessed using a kindling model induced by pentylenetetrazol (PTZ) in mice. A total of six groups were formed, each consisting of nine mice, and the animals were randomly allocated. PTZ (25 mg/kg, i.p.) was administered on alternate days for six weeks. Montelukast (MTK) was evaluated at three dose levels (5, 10, and 20 mg/kg, i.p.), while levetiracetam (30 mg/kg, i.p.) served as a standard comparator. Montelukast (20 mg/kg) significantly lowered seizure severity (lower Racine scale scores) and improved cognition in both the elevated plus maze and passive avoidance assessments. Biochemical assessments revealed enhanced catalase activity, reduced glutamate, and elevated γ-aminobutyric acid (GABA) concentrations. Furthermore, montelukast significantly decreases pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), along with other mediators of neuroinflammation such as high-mobility group box-1 (HMGB1), transforming growth factor-β (TGF-β), matrix metalloproteinase-9 (MMP9), and toll-like receptor-4 (TLR-4).Histopathological analysis confirmed that administration of montelukast protected cortical and hippocampal integrity by reducing neuronal damage. Collectively, these findings suggest that montelukast exhibits anticonvulsant and neuroprotective potential in a PTZ model and supports further investigation in epilepsy.