Diosmetin's impact on epileptic seizures: a study on inflammatory pathways and neuronal health

Abstract

This study investigated the anti-seizure potential of diosmetin (DM), a naturally occurring active compound, and explored its molecular mechanisms. A pentetrazole (PTZ)-induced chemical kindling mouse model was employed to assess seizure severity, cognitive function, motor coordination, and anxiety-like behaviors. Hippocampal neuronal injury was examined by hematoxylin–eosin and Nissl staining. In addition, an in vitro seizure model was established in PC12 cells using Mg²⁺-free extracellular fluid to evaluate the effects of DM on cell viability and apoptosis. Levels of inflammatory mediators were measured by ELISA, while Western blotting and RT-qPCR were used to analyze the expression of NLRP3-ASC-Caspase-1 inflammasome–related proteins and genes. The expression of SIRT1 at both mRNA and protein levels was further examined, and the role of SIRT1 was validated using specific inhibitors. Results demonstrated that DM significantly reduced seizure intensity in epileptic mice. Additionally, it improved learning and memory, enhanced motor performance, and alleviated anxiety-like behaviors. Histological analysis confirmed that DM markedly alleviated hippocampal neuronal damage. In PC12 cells, DM increased cell survival and reduced apoptosis. Mechanistic studies revealed that DM suppressed inflammatory cytokines such as IL-1β and IL-18, elevated anti-inflammatory IL-10, downregulated inflammasome signaling, and upregulated SIRT1 expression. Inhibition of SIRT1 reversed these protective effects, indicating that DM acts via SIRT1-mediated pathways. Collectively, these findings suggest that DM mitigates epilepsy-induced neuroinflammation and functional impairments, supporting its potential as a preclinical candidate for adjunctive therapy in epilepsy.