SELECTED PEPTIDES TARGETED TO THE NMDA RECEPTOR-CHANNEL PROTECT NEURONS FROM EXCITOTOXIC DEATH

Excitotoxic neuronal death, associated with neurodegeneration and stro ke, is triggered primarily by massive Ca2+ influx arising from overact ivation of glutamate receptor channels of the N-methyl-D-aspartate (NM DA) subtype. To search for channel blockers, synthetic combinatorial l ibraries were assayed for block of agonist-evoked currents by the huma n NR1-NR2A NMDA receptor subunits expressed in amphibian oocytes. A se t of arginine-rich hexapeptides selectively blocked the NMDA receptor channel with IC50 approximately 100 nM, a potency similar to clinicall y tolerated blockers such as memantine, and only marginally blocked on non-NMDA glutamate receptors. These peptides prevent neuronal cell de ath elicited by an excitotoxic insult on hippocampal cultures.