Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions.
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.
Aarts
Michelle
M
Toronto Western Hospital Research Institute, 11-416 MC-PAV, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Liu
Yitao
Y
Liu
Lidong
L
Besshoh
Shintaro
S
Arundine
Mark
M
Gurd
James W
JW
Wang
Yu-Tian
YT
Salter
Michael W
MW
Tymianski
Michael
M
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
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