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

• Published in: Journal of cerebral blood flow and metabolism 2016-09, Vol.36 (9), p.1508-1512
• Main Authors: Kleinschnitz, Christoph, Mencl, Stine, Kleikers, Pamela WM, Schuhmann, Michael K, G López, Manuela, Casas, Ana I, Sürün, Bilge, Reif, Andreas, Schmidt, Harald HHW
• Format: Article
• Language: English
• Subjects: Animals; Brain Injuries - prevention & control; Brain Ischemia - prevention & control; Brief Communications; 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
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X16657094

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.