title: Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.
abstract: 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.
authors.affiliation: Toronto Western Hospital Research Institute, 11-416 MC-PAV, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Aarts
authors.forename: Yitao
authors.initials: Y
authors.lastname: Liu
authors.forename: Lidong
authors.initials: L
authors.lastname: Liu
authors.forename: Shintaro
authors.initials: S
authors.lastname: Besshoh
authors.forename: Mark
authors.initials: M
authors.lastname: Arundine
authors.forename: James W
authors.initials: JW
authors.lastname: Gurd
authors.forename: Yu-Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins; D016202:N-Methylaspartate; D051528:Guanylate Kinases; D006152:Cyclic GMP; D002118:Calcium