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

• Published in: Science (American Association for the Advancement of Science) 2002-10, Vol.298 (5594), p.846-850
• Main Authors: Aarts, Michelle, Liu, Yitao, Liu, Lidong, Besshoh, Shintaro, Arundine, Mark, Gurd, James W., Wang, Yu-Tian, Salter, Michael W., Tymianski, Michael
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Brain; Brain - drug effects; Brain - metabolism; Brain damage; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Calcium - metabolism; Cells, Cultured; Cerebral infarction; Cerebral Infarction - drug therapy; Cerebral Infarction - metabolism; Cyclic GMP - metabolism; Disks Large Homolog 4 Protein; Fluorescence; Guanylate Kinases; In Vitro Techniques; Individualized Instruction; Insults; Intracellular Signaling Peptides and Proteins; Literary Devices; Male; Medical sciences; Membrane Proteins; Mice; Mice, Inbred C57BL; N-Methylaspartate - pharmacology; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurological Impairments; Neurology; Neurons; Neurons - drug effects; Neurons - physiology; Patch-Clamp Techniques; Peptides; Peptides - administration & dosage; Peptides - pharmacology; Peptides - therapeutic use; Pretreatment; Protein Binding; Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Rodents; Signal Transduction; Stroke; Strokes; Synaptic Transmission - drug effects; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1072873

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.