NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage

J Cereb Blood Flow Metab. 2016 Sep;36(9):1508-12. doi: 10.1177/0271678X16657094. Epub 2016 Jun 28.


Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1(-/-) mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.

Keywords: Nitric oxide; excitotoxicity; experimental; free radicals; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / prevention & control*
  • Brain Ischemia / prevention & control*
  • Disks Large Homolog 4 Protein
  • Enzyme Inhibitors / pharmacology
  • Guanylate Kinases / antagonists & inhibitors*
  • Guanylate Kinases / metabolism
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Neuroprotective Agents / pharmacology
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type I / metabolism
  • Protein Binding


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Enzyme Inhibitors
  • Membrane Proteins
  • Neuroprotective Agents
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • Guanylate Kinases