Combined Inhibition of TRPM4/NMDA Receptor Complex and Extrasynaptic NMDA Receptors Is Candidate Therapeutic Target for Suppression of Epileptic Seizures and Improvement of Cognitive Impairments.

Abstract

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.