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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}, mike.salter{at}

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X. You, A. W. Nguyen, A. Jabaiah, M. A. Sheff, K. S. Thorn, and P. S. Daugherty (2006)
PNAS 103, 18458-18463
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Opposite Effects of PSD-95 and MPP3 PDZ Proteins on Serotonin 5-Hydroxytryptamine2C Receptor Desensitization and Membrane Stability.
S. Gavarini, C. Becamel, C. Altier, P. Lory, J. Poncet, J. Wijnholds, J. Bockaert, and P. Marin (2006)
Mol. Biol. Cell 17, 4619-4631
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NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity.
B. Picconi, A. Tortiglione, I. Barone, D. Centonze, F. Gardoni, P. Gubellini, P. Bonsi, A. Pisani, G. Bernardi, M. Di Luca, et al. (2006)
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A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia..
F. Gardoni, B. Picconi, V. Ghiglieri, F. Polli, V. Bagetta, G. Bernardi, F. Cattabeni, M. Di Luca, and P. Calabresi (2006)
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Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence.
D.-S. Pei, X.-T. Wang, Y. Liu, Y.-F. Sun, Q.-H. Guan, W. Wang, J.-Z. Yan, Y.-Y. Zong, T.-L. Xu, and G.-Y. Zhang (2006)
Brain 129, 465-479
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Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition: A TARGET FOR NEUROPROTECTION IN THE CENTRAL NERVOUS SYSTEM.
A. Siddiq, I. A. Ayoub, J. C. Chavez, L. Aminova, S. Shah, J. C. LaManna, S. M. Patton, J. R. Connor, R. A. Cherny, I. Volitakis, et al. (2005)
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Nucleus Accumbens Long-Term Depression and the Expression of Behavioral Sensitization.
K. Brebner, T. P. Wong, L. Liu, Y. Liu, P. Campsall, S. Gray, L. Phelps, A. G. Phillips, and Y. T. Wang (2005)
Science 310, 1340-1343
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Mitochondrial Nitric Oxide Mediates Decreased Vulnerability of Hippocampal Neurons from Immature Animals to NMDA.
J. D. Marks, C. Boriboun, and J. Wang (2005)
J. Neurosci. 25, 6561-6575
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BIRB796 Inhibits All p38 MAPK Isoforms in Vitro and in Vivo.
Y. Kuma, G. Sabio, J. Bain, N. Shpiro, R. Marquez, and A. Cuenda (2005)
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Protein-Protein Coupling/Uncoupling Enables Dopamine D2 Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity.
S. Zou, L. Li, L. Pei, B. Vukusic, H. H. M. Van Tol, F. J. S. Lee, Q. Wan, and F. Liu (2005)
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TRPM7 and Ischemic CNS Injury.
M. M. Aarts and M. Tymianski (2005)
Neuroscientist 11, 116-123
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Apoptosis-Inducing Factor Is a Key Factor in Neuronal Cell Death Propagated by BAX-Dependent and BAX-Independent Mechanisms.
E. C. C. Cheung, L. Melanson-Drapeau, S. P. Cregan, J. L. Vanderluit, K. L. Ferguson, W. C. McIntosh, D. S. Park, S. A. L. Bennett, and R. S. Slack (2005)
J. Neurosci. 25, 1324-1334
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N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease.
E. A. Waxman and D. R. Lynch (2005)
Neuroscientist 11, 37-49
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The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death.
J. Cao, J. I. Viholainen, C. Dart, H. K. Warwick, M. L. Leyland, and M. J. Courtney (2005)
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A Novel Ca2+-Independent Signaling Pathway to Extracellular Signal-Regulated Protein Kinase by Coactivation of NMDA Receptors and Metabotropic Glutamate Receptor 5 in Neurons.
L. Yang, L. Mao, Q. Tang, S. Samdani, Z. Liu, and J. Q. Wang (2004)
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Differential Mechanisms of Nitric Oxide- and Peroxynitrite-Induced Cell Death.
J. T. A. Meij, C. L. Haselton, K. L. Hillman, D. Muralikrishnan, M. Ebadi, and L. Yu (2004)
Mol. Pharmacol. 66, 1043-1053
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Vulnerability of Central Neurons to Secondary Insults after In Vitro Mechanical Stretch.
M. Arundine, M. Aarts, A. Lau, and M. Tymianski (2004)
J. Neurosci. 24, 8106-8123
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Protein Kinase C {delta} Mediates Cerebral Reperfusion Injury In Vivo.
R. Bright, A. P. Raval, J. M. Dembner, M. A. Perez-Pinzon, G. K. Steinberg, M. A. Yenari, and D. Mochly-Rosen (2004)
J. Neurosci. 24, 6880-6888
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Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules.
M. H. A. Roehrl, S. Kang, J. Aramburu, G. Wagner, A. Rao, and P. G. Hogan (2004)
PNAS 101, 7554-7559
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ABAD Directly Links A{beta} to Mitochondrial Toxicity in Alzheimer's Disease.
J. W. Lustbader, M. Cirilli, C. Lin, H. W. Xu, K. Takuma, N. Wang, C. Caspersen, X. Chen, S. Pollak, M. Chaney, et al. (2004)
Science 304, 448-452
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Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-D-aspartate Receptor.
G. A. Rameau, L.-Y. Chiu, and E. B. Ziff (2004)
J. Biol. Chem. 279, 14307-14314
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