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Article: Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95

TitleTreatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95
Authors
Issue Date2010
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nm
Citation
Nature Medicine, 2010, v. 16 n. 12, p. 1439-1444 How to Cite?
AbstractStroke is a major public health problem leading to high rates of death and disability in adults. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS-"PSD-95 interaction via overexpressing the N-terminal amino acid residues 1-"133 of nNOS (nNOS-N 1-"133) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS-"PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS-"PSD-95 association selectively, had potent neuroprotective activity in vitro and ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects. © 2010 Nature America, Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/168494
ISSN
2015 Impact Factor: 30.357
2015 SCImago Journal Rankings: 13.959
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorZhou, Len_US
dc.contributor.authorLi, Fen_US
dc.contributor.authorXu, HBen_US
dc.contributor.authorLuo, CXen_US
dc.contributor.authorWu, HYen_US
dc.contributor.authorZhu, MMen_US
dc.contributor.authorLu, Wen_US
dc.contributor.authorJi, Xen_US
dc.contributor.authorZhou, QGen_US
dc.contributor.authorZhu, DYen_US
dc.date.accessioned2012-10-08T03:19:38Z-
dc.date.available2012-10-08T03:19:38Z-
dc.date.issued2010en_US
dc.identifier.citationNature Medicine, 2010, v. 16 n. 12, p. 1439-1444en_US
dc.identifier.issn1078-8956en_US
dc.identifier.urihttp://hdl.handle.net/10722/168494-
dc.description.abstractStroke is a major public health problem leading to high rates of death and disability in adults. Excessive stimulation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation are crucial for neuronal injury after stroke insult. However, directly inhibiting NMDARs or nNOS can cause severe side effects because they have key physiological functions in the CNS. Here we show that cerebral ischemia induces the interaction of nNOS with postsynaptic density protein-95 (PSD-95). Disrupting nNOS-"PSD-95 interaction via overexpressing the N-terminal amino acid residues 1-"133 of nNOS (nNOS-N 1-"133) prevented glutamate-induced excitotoxicity and cerebral ischemic damage. Given the mechanism of nNOS-"PSD-95 interaction, we developed a series of compounds and discovered a small-molecular inhibitor of the nNOS-PSD-95 interaction, ZL006. This drug blocked the ischemia-induced nNOS-"PSD-95 association selectively, had potent neuroprotective activity in vitro and ameliorated focal cerebral ischemic damage in mice and rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Moreover, it readily crossed the blood-brain barrier, did not inhibit NMDAR function, catalytic activity of nNOS or spatial memory, and had no effect on aggressive behaviors. Thus, this new drug may serve as a treatment for stroke, perhaps without major side effects. © 2010 Nature America, Inc. All rights reserved.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nmen_US
dc.relation.ispartofNature Medicineen_US
dc.subject.meshAnalysis Of Varianceen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBiological Transport - Physiologyen_US
dc.subject.meshBrain Ischemia - Complications - Drug Therapy - Metabolismen_US
dc.subject.meshCell Death - Drug Effects - Physiologyen_US
dc.subject.meshGlutamic Aciden_US
dc.subject.meshGuanylate Kinaseen_US
dc.subject.meshImmunoprecipitationen_US
dc.subject.meshInfarction, Middle Cerebral Artery - Drug Therapyen_US
dc.subject.meshIntracellular Signaling Peptides And Proteins - Metabolismen_US
dc.subject.meshMembrane Proteins - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMicroscopy, Confocalen_US
dc.subject.meshMolecular Structureen_US
dc.subject.meshNeuroprotective Agents - Metabolism - Pharmacology - Therapeutic Useen_US
dc.subject.meshNitric Oxide Synthase Type I - Chemistry - Metabolismen_US
dc.subject.meshOligonucleotides, Antisense - Metabolism - Pharmacology - Therapeutic Useen_US
dc.subject.meshRatsen_US
dc.subject.meshReceptors, N-Methyl-D-Aspartate - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshSignal Transduction - Drug Effects - Physiologyen_US
dc.subject.meshStroke - Drug Therapy - Etiologyen_US
dc.titleTreatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95en_US
dc.typeArticleen_US
dc.identifier.emailLu, W:luwei@hku.hken_US
dc.identifier.authorityLu, W=rp00754en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/nm.2245en_US
dc.identifier.pmid21102461-
dc.identifier.scopuseid_2-s2.0-78649983743en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78649983743&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume16en_US
dc.identifier.issue12en_US
dc.identifier.spage1439en_US
dc.identifier.epage1444en_US
dc.identifier.isiWOS:000285048900039-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridZhou, L=7404125996en_US
dc.identifier.scopusauthoridLi, F=36079222200en_US
dc.identifier.scopusauthoridXu, HB=37035381200en_US
dc.identifier.scopusauthoridLuo, CX=10244933800en_US
dc.identifier.scopusauthoridWu, HY=35771869100en_US
dc.identifier.scopusauthoridZhu, MM=7402908747en_US
dc.identifier.scopusauthoridLu, W=27868087600en_US
dc.identifier.scopusauthoridJi, X=35200612800en_US
dc.identifier.scopusauthoridZhou, QG=7402699662en_US
dc.identifier.scopusauthoridZhu, DY=7403598907en_US
dc.identifier.citeulike8384083-

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