Dapagliflozin/ Carveol Combination Ameliorates Pentylenetetrazole Induced Epilepsy in Rats: Antioxidant, Anti-Inflammatory and Anti-Apoptotic Effects: Targeting TLR4/miR-181b/NFkB

Background: Epilepsy is a significant public health problem, which encompasses socio-cultural, psychological, and economic dimensions. Dapagliflozin is an SGLT2 inhibitor that has antiseizure activity. Carveol is a naturally occurring monocyclic monoterpenoid compound with antioxidant properties. This study examines the impacts of Dapagliflozin and Carveol, either monotherapy or in combination, on PTZ-induced epilepsy in rats. Methods: 45 Male Wistar rats were randomly categorized in 5 equal groups: Group I: Control Group, Group II: PTZ Group, Group III: Dapagliflozin-Treated Group, Group IV: Carveol-Treated Group and Group V: Dapagliflozin + Carveol Treated Group. Hippocampal tissues were obtained for assay of tissue biomarkers including, SOD, MDA, NFκB, IL-6, TNF-alpha, Beclin-1, GABA, glutamate, gene expression of TLR4, miR-181b, NKCC1 and KCC2, immunohistochemical analysis of caspase 3 and histopathological analysis. Results: Dapagliflozin and Carveol treated group (Group V) ameliorated PTZ induced epilepsy evidenced by increased GABA, decreased glutamate, improvement of histopathology and oxidative stress via upregulation of SOD and downregulation of MDA, improved inflammation via significant reduction of NFκB, IL-6, TNF-α. Moreover, modulation of apoptosis and autophagy process via significant reduction of caspase3, TLR4 gene expression and up regulation of miR-181b gene expression and beclin-1, a significant increase in GABA and gene expression of KCC2 accompanied with a significant decrease in glutamate and gene expression of NKCC1, compared to other groups. Conclusion: The combination of Dapagliflozin and Carveol exhibited significantly better antioxidant, anti-inflammatory and anti-apoptotic effects than monotherapy by either of each of both drugs against PTZ induced epilepsy.