부산대학교 도서관

Abstract Inhibition of postsynaptic density protein-95 (PSD-95) decouples N -methyl- d -aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials. Highlights • The dimeric PSD-95 inhibitor UCCB01-144 potently binds all four PSD-95-like MAGUKs. • UCCB01-144 affects NMDA receptor signaling pathways in ischemic brain tissue. • UCCB01-144 at 30 min, but not 60 min, post-ischemia reduces infarcts at various doses. • UCCB01-144 reduces infarcts in young and aged mice, but not in females or at high dose. • High dose UCCB01-144 gives no cardiovascular side effects in contrast to Tat-NR2B9c. [ABSTRACT FROM AUTHOR]