INTRODUCTION: Glucose dysregulation increases seizure susceptibility and underlies systemic complications in epilepsy.

AIM(S): This study evaluated common pathogenesis markers in a PTZ-induced kindling model and assessed the therapeutic potential of targeting mTOR and PPAR-γ pathways.

METHOD(S): Wistar rats underwent a 21-day PTZ-kindling protocol. Treatment groups received daily administration of Rapamycin (mTOR inhibitor), Pioglitazone (PPAR-γ agonist), or a combination of both, starting after the 11th PTZ injection. Seizure severity was assessed daily. Post-experimental analysis included biochemical screening (glucose, insulin, HOMA-IR), brain TRPV1 content measurement, and histomorphological evaluation of myocardial and liver tissues.

RESULTS: Combined therapy protected 5/7 rats from generalized seizures. Kindled rats showed hyperglycemia (+28.6%), hyperinsulinemia (+47.0%), and a 62.0% increase in HOMA-IR compared to controls. Combined treatment reversed these metabolic shifts, whereas Rapamycin alone was ineffective. Brain TRPV1 levels rose by 40.5% in kindled rats but decreased by 38.0% after combined therapy. Furthermore, combined treatment prevented systemic damage, including myocardial microhemorrhages, cardiomyocyte thickening, and perivenular liver fibrosis with Kupffer cell infiltration, which were observed in untreated kindled rats.

CONCLUSIONS: Our findings highlight that chronic kindling induces significant systemic impairments, including hyperglycemia, hyperinsulinemia, and peripheral organ damage (heart and liver). A short-term course of pioglitazone, intensified by rapamycin, not only reduces seizure severity but also mitigates these diabetes-related manifestations. This suggests that targeting metabolic pathways and transient receptor potential channels (TRPV1) may offer a novel multi-target strategy for managing epileptic comorbidities.

FINANCIAL SUPPORT: Supported by the internal research budget of Odesa National Medical University