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

Nat Med. 2010 Dec;16(12):1439-43. doi: 10.1038/nm.2245. Epub 2010 Nov 21.


Stroke 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Biological Transport / physiology
  • Brain Ischemia / complications
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Disks Large Homolog 4 Protein
  • Glutamic Acid
  • Guanylate Kinases
  • Immunoprecipitation
  • Infarction, Middle Cerebral Artery / drug therapy
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Microscopy, Confocal
  • Molecular Structure
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Nitric Oxide Synthase Type I / chemistry
  • Nitric Oxide Synthase Type I / metabolism*
  • Oligonucleotides, Antisense / metabolism
  • Oligonucleotides, Antisense / pharmacology*
  • Oligonucleotides, Antisense / therapeutic use
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Stroke / drug therapy*
  • Stroke / etiology


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neuroprotective Agents
  • Oligonucleotides, Antisense
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Nitric Oxide Synthase Type I
  • Guanylate Kinases