Targeting PSD-95 as a Novel Approach in the Treatment of Stroke

Abstract

During ischemia and stroke, a large excess of glutamate is released from the presynaptic terminal into the synaptic cleft. The NMDA receptor is activated by glutamate in the presence of glycine and triggers an influx of Ca2+ and hence induces excitotoxicity. PSD-95 is a scaffolding protein comprising three PDZ domains, one SH3 and one GK domain, which modulates numerous physiological relevant protein--protein interactions by interacting with the C-terminus or an internal binding motif of protein partners. The GluN2B subunit of the NMDA receptor and nNOS forms a ternary complex together with PSD-95 by interacting with PDZ1 and PDZ2 of PSD-95, respectively. Upon Ca2+ influx, this ternary complex induces the production of the toxic substance nitric oxide and further on ischemic brain damage. Numerous attempts and strategies have been applied to inhibit PSD-95/nNOS/NMDA receptor-induced excitotoxicity. Here we will present previous and ongoing efforts to develop and evaluate peptide, peptidomimetics and small molecule inhibitors targeting PSD-95.