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Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions
Michelle Aarts,1*Yitao Liu,234*Lidong Liu,234Shintaro Besshoh,5Mark Arundine,1James W. Gurd,5Yu-Tian Wang,234Michael W. Salter,36Michael Tymianski167
N-methyl-D-aspartate
receptors (NMDARs) mediate ischemic brain damage but also
mediate essential neuronal excitation. To treatstroke without blocking
NMDARs, we transduced neurons with peptidesthat disrupted the
interaction of NMDARs with the postsynapticdensity protein PSD-95.
This procedure dissociated NMDARs fromdownstream neurotoxic signaling
without blocking synaptic activityor calcium influx. The peptides,
when applied either before or1 hour after an insult, protected
cultured neurons from excitotoxicity,reduced focal ischemic brain
damage in rats, and improved theirneurological function. This approach
circumvents the negativeconsequences associated with blocking NMDARs
and may constitutea 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.
To whom correspondence should be addressed.
E-mail: mike_t{at}uhnres.utoronto.ca,
mike.salter{at}utoronto.ca
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