Neuroprotective and anticonvulsant effect of trimetazidine in a PTZ-kindling model of mice through modulation of the IL-1β/IL-1R1 and HMGB-1/TLR-4 axis.

Background: Epilepsy is a chronic and complex brain disorder characterized by frequent seizures, cognitive impairments, neuroinflammation, oxidative stress, and imbalances in neurotransmitters. Developing an effective therapeutic intervention to target these pathological interventions remains a challenge. Trimetazidine (TMZ), the most commonly known anti-ischemic agent, has emerged as a promising candidate for its role in epilepsy due to its diverse mechanisms of action. This study investigates the neuroprotective, anticonvulsant, anti-inflammatory, antioxidant, and neuromodulatory effects of TMZ in managing epilepsy. Methods: Kindling was induced by administering Pentylenetetrazole (30 mg/kg, Results: TMZ, primarily at 10 and 20 mg/kg, significantly reduced seizure scores and improved the transfer latency, step-down latency, and motor abilities in the PTZ-kindled animals. It significantly reduced proinflammatory molecules IL-1β, IL-1R1, IL-6, NF-κB, TNF-α, HMGB-1, TLR-4. Additionally, it increased antioxidant enzyme activity (GSH, SOD, catalase) while lowering MDA levels and restoring GABA, dopamine, and serotonin levels, as well as suppressing glutamate levels, comparable to VPA at 200 mg/kg/day Conclusion: TMZ, at doses of 10 and 20 mg/kg p.o., demonstrated anticonvulsant and antioxidant activity, suppressed kindling progression, and restored neurotransmitter balance. Furthermore, TMZ has shown anti-inflammatory activity against neuroinflammation during epilepsy.