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Science 298 (5594): 846-850

Copyright © 2002 by the American Association for the Advancement of Science

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

Michelle Aarts,1* Yitao Liu,234* Lidong Liu,234 Shintaro Besshoh,5 Mark Arundine,1 James W. Gurd,5 Yu-Tian Wang,234 Michael W. Salter,36dagger Michael Tymianski167dagger

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.

1 Toronto Western Hospital Research Institute, 11-416 MC-PAV, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
2 Divisions of Laboratory Medicine and Pathobiology,
3 Programme in Brain and Behaviour, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
4 Brain Research Center and Department of Medicine, Vancouver Hospital and Health Sciences Center, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
5 Centre for the Neurobiology of Stress, Division of Life Sciences, University of Toronto at Scarborough, Toronto, Ontario M1C 1A3, Canada.
6 Department of Physiology,
7 Department of Surgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: mike_t{at}uhnres.utoronto.ca, mike.salter{at}utoronto.ca



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