Fluvoxamine Attenuates Blood-Brain Barrier Disruption in Drug-Resistance Epilepsy and inhibits Ferroptosis via the Sigma-1 Receptor-TAMM41 signaling in bEnd.3 cells

Drug resistance is common in epileptic patients, necessitating the exploration of novel therapeutic strategies to convert drug resistance into drug responsiveness. The repurposing of existing drugs has emerged as an attractive approach for finding novel drugs. In this study, we utilized a combination of network computation and text mining techniques to identify potential repurposable drugs for treating drug-resistant epilepsy (DRE) and elucidate the underlying mechanisms. Our analysis identified fluvoxamine as a promising candidate for repurposing in epilepsy treatment. Using the lamotrigine-pentylenetetrazol kindling drug-resistant epilepsy model, we found that fluvoxamine effectively converted drug-resistant epilepsy in mice to drug responsiveness, including against gabapentin, phenytoin sodium, and carbamazepine. Additionally, fluvoxamine mitigated the elevated blood-brain barrier permeability associated with drug-resistant epilepsy by activating the sigma-1 receptor (S1R). Furthermore, fluvoxamine inhibited ferroptosis in endothelial cells induced by kainic acid. Proteome test revealed that fluvoxamine increased the expression of TAM41 Mitochondrial Translocator Assembly And Maintenance Homolog (TAMM41), a protein located in the inner mitochondrial membrane of endothelial cells. Notably, the knockdown or conditional knockout of TAMM41 in brain microvascular endothelial cells (BMVECs) reversed the protective effects of fluvoxamine on the blood-brain barrier (BBB) integrity and its inhibitory action on ferroptosis. In contrast, fluoxetine, despite sharing similar pharmacokinetic features and receptor spectrum with fluvoxamine, didn’t elevate TAMM41 levels or exhibit anti-drug-resistant epileptic activity. Collectively, our findings demonstrate that fluvoxamine restores the responsiveness of DRE mice to antiepileptic drugs, alleviates BBB impairment, and inhibits BMVECs ferroptosis by activating the S1R-TAMM41 axis in BMVECs. Given the critical role of BBB disruption in drug-resistant epilepsy pathogenesis, this study may offer novel therapeutic strategies for treating drug-resistant epilepsy.