Development of a Reactive Oxygen Species-Sensitive Nitric Oxide Synthase Inhibitor for the Treatment of Ischemic Stroke.

In this study, the nitrone 5was designed such that its decomposition product is a NOS inhibitor, 6, effectively leading to NOS inhibition specifically at the site of ROS production. The ability of 5to spin-trap radicals and decompose to 6 was observed using EPR and LC-MS/MS. The pro-drug concept was tested in vitro by measuring cell viability and 6 formation in SH-SY5Y cells subjected to oxygen glucose deprivation (OGD). 5 was found to be more efficacious and more potent than PBN, and was able to increase phospho-Akt while reducing nitrotyrosine and cleaved caspase-3 levels. 6 treatment, but not 5, was found to decrease NO production in LPS-stimulated microglia. Doppler flowmetry on anesthetized mice showed an increased cerebral blood flow upon intravenous administration of 1mg/kg 5, but a return to baseline upon administration of 10mg/kg, likely due to its dual nature of antioxidant/NO-donor and NOS-inhibition. Mice treated with 5 after permanent ischemia exhibited a >30% reduction in infarct volume, and higher formation 6 in ischemic tissue resulting in region specific effects limited to the infarct area. PMID: 29275014 [PubMed - as supplied by publisher]
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research