MCC-135 Exerts Antiepileptic and Neuroprotective Effects by Downregulating NCX1 Expression to Decrease Intracellular Calcium Overload in the Hippocampus.

Abstract

BACKGROUND: Approximately 30% of epilepsy patients still develop drug resistance after standard antiepileptic treatment. Therefore, there is an urgent need to identify new drug targets to improve seizure control. Previous studies have shown that NCX1 can regulate the intracellular Calevels in astrocytes and neurons, which are closely associated with epilepsy. MCC-135 has shown potential as an antiseizure medication due to its ability to downregulate NCX and reduce intracellular calcium overload; however, its role and mechanism in epilepsy remain unclear. METHODS: This study employed single-cell analysis and molecular docking to identify the potential molecular targets of MCC-135 in treating epilepsy. Additionally, we used a KA-induced epileptic mouse model to validate these molecular levels and the therapeutic effects and mechanisms of MCC-135. RESULTS: Relative to controls, NCX1 expression was significantly upregulated in the hippocampus of KA-induced epileptic mice. Immunofluorescence staining revealed that NCX1 was co-localized with both astrocytes and neurons. MCC-135 treatment significantly prolonged the seizure latency in KA-induced epileptic mice and alleviated hippocampal neuronal damage. Furthermore, MCC-135 effectively reduced NCX1 expression, alleviated intracellular calcium overload, and downregulated glutamate levels in the epileptic mice. CONCLUSION: MCC-135 exerts neuroprotective and antiepileptic effects by downregulating NCX1 expression, thereby alleviating calcium overload and reducing glutamate levels in the hippocampus. We are the first to propose the role and mechanism of MCC-135 in epilepsy treatment, providing novel insights into its potential as a therapeutic agent for epilepsy.