Research reportProtection of neuronal cells from excitotoxicity by disrupting nNOS-PSD95 interaction with a small molecule SCR-4026

•SCR-4026 disrupts nNOS-PSD-95 association with an IC50 of 6.3 μM in vitro.•SCR-4026 shows dose-dependent neuroprotective activities in NMDA and OGD model.•Treatment with SCR-4026 results in decreased nNOS-PSD-95 association in NMDA model.•SCR-4026 promotes neural precursor cells to differentiate into neurons-like cells.•Treatment with SCR-4026 alleviates brain injury in rat MCAO model.

Stroke is a major public health problem leading to high rates of death and disability in adults. Coupling of postsynaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) plays an important part in neuronal damage caused by stroke. Recent studies suggest the possibility of alleviating post ischemia neuron damage by blocking ischemia-induced nNOS-PSD-95 association. Here, we report a small-molecular inhibitor of nNOS-PSD-95 interaction, SCR-4026, which exhibits neuroprotective activities in NMDA-induced or Oxygen and glucose deprivation (OGD)-induced neuronal damage in primary cortical neurons cultures, and ameliorated focal cerebral ischemic damage in rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Furthermore, we found that SCR-4026 was also able to promote neural stem cells to differentiate into neurons-like cells, which is potentially of great significance for neural protection. Taken together, SCR-4026 is identified as a novel small molecule that shows great potential in treating stroke.