Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions

作者：Michelle M. Aarts, Yitao Liu, Lidong Liu, Shintaro Besshoh, Mark Arundine, James W. Gurd, Yu-Tian Wang, Michael W. Salter, Michael Tymianski · 发表于：Science · 年份：2002 · DOI：10.1126/science.1072873 · 被引用次数：1005 · 研究领域：Neuroscience and Neuropharmacology Research、RNA Interference and Gene Delivery、Chemical Synthesis and Analysis

N-methyl-D-aspartate receptors (NMDARs) mediate ischemic brain damage but also mediate essential neuronal excitation. To treat stroke without blocking NMDARs, we transduced neurons with peptides that disrupted the interaction of NMDARs with the postsynaptic density protein PSD-95. This procedure dissociated NMDARs from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurological function. This approach circumvents the negative consequences associated with blocking NMDARs and may constitute a practical stroke therapy.