Ameliorative effect of glycyrrhizin in mitochondrial drug-resistant epilepsy: role of HMGB1 inhibition.

Abstract

Epilepsy affects millions of individuals worldwide, with a significant proportion experiencing drug-resistant epilepsy (DRE) despite the availability of antiepileptic drugs (ASDs). High mobility group box 1 (HMGB1), a nuclear protein involved in inflammation and immune responses, has a significant role in the pathogenesis of epilepsy. Glycyrrhizin, a triterpene glycoside derived from liquorice root, has shown anti-inflammatory and neuroprotective properties by inhibiting HMGB1 release. However, its potential as an HMGB1 inhibitor in DRE remains unexplored. Swiss albino mice underwent rotenone corneal kindling for 15 days to induce DRE. Pretreatment resistance validation was done using standard ASDs followed by treatment with glycyrrhizin (10, 20, and 40 mg/kg) for 15 days. Further post-treatment resistance validation was done and the animal was sacrificed on the 40th day. Results suggest that the level of TBARS, HMGB1, IL6, and glutamate has been elevated; conversely, the GSH level has reduced in the RCK group compared to naïve. Standard ASDs have shown significant resistance in the RCK group before treatment with glycyrrhizin. Furthermore, glycyrrhizin showed an antioxidant and anti-inflammatory effect as evidenced by reduced oxidative stress and HMGB1 and IL6 levels. Moreover, a reduced seizure severity score was observed after post-treatment resistance validation with the same standard ASDs. Glycyrrhizin significantly reduced seizure severity by inhibiting the HMGB1-TLR4 signalling pathway in the rotenone-corneal kindling model, highlighting HMGB1 inhibition as a promising therapeutic target for drug-resistant epilepsy.