Combined Inhibition of <scp>TRPM</scp> 4/ <scp>NMDA</scp> Receptor Complex and Extrasynaptic <scp>NMDA</scp> Receptors Is Candidate Therapeutic Target for Suppression of Epileptic Seizures and Improvement of Cognitive Impairments

Cognitive impairments are important therapeutic targets in epilepsy medication; however, effective pharmacological treatments for epilepsy patients with comorbid cognitive impairment have not been established. Effects of chronic administration of MK-801 (noncompetitive NMDA receptor inhibitor), memantine (low-affinity extrasynaptic-NMDA receptor preferential inhibitor), FP802 (TwinF interface inhibitor), and probenecid (pannexin1 containing hemichannel inhibitor) for 14 days on epileptic seizure frequency, sucrose preference, extracellular levels of L-glutamate and D-serine, expression of GluN2A and GluN2B, and phosphorylated CREB levels in the frontal cortex (epileptic focus region) were investigated using a genetic rat model of epilepsy with cognitive impairment (S286L-TG rats). Seizure frequency of S286L-TG was reduced by chronic administration of probenecid, MK-801, and memantine + FP802, but not by memantine or FP802 alone. Decreased sucrose preference of S286L-TG relative to wild-type littermate rats was restored by memantine and memantine + FP802, but aggravated by MK-801 without being affected by probenecid or FP802. Downregulated GluN2A/GluN2B expression in S286L-TG relative to wild-type was restored by probenecid, memantine, and memantine + FP802, but further decreased by MK-801, and was unaffected by FP802. Upregulated basal extracellular L-glutamate/D-serine levels in S286L-TG were restored by probenecid and memantine + FP802, further increased by MK-801, and unaffected by FP802. In contrast, chronic memantine alone restored the basal D-serine increasing but did not affect basal L-glutamate. These results suggest the possibility that a combination of suppressing TRPM4/NMDA receptor complex and extrasynaptic NMDA receptor may contribute to reducing epileptic seizures and ameliorating dysfunction/bias of preference regulation, providing a potential therapeutic strategy for epilepsy patients comorbid with cognitive impairments.