Treatment of Ischemic Stroke with ROS-Sensitive Nitric Oxide Synthase Inhibitors
Project ID: D2018-11 Background Nearly 800,000 people in the United States suffer a stroke every year, with about 87% of the strokes being classified as ischemic. Ischemic stroke is caused by blockage of blood flow to the brain, which results in neuronal and glial hypoxia and, subsequently, inflammatory and free radical-mediated cell death. Reactive oxygen species (ROS) formed in excess under the hypoxic conditions cause protein, DNA and lipid oxidation. Nitric oxide (NO) via NO synthase (NOS) is known to be protective in ischemic stroke, however, NOS has been shown to ‘uncouple’ under oxidative conditions to, instead, produce superoxide. Nitrones are antioxidant molecules that have been shown to trap ROS to decompose and release NO. However, synthetic nitrones and NOS inhibitors have thus far failed to yield favorable outcomes in diseases. Invention DescriptionResearchers at the University of Toledo, led by Dr. Kevin Nash, have developed a class of molecules that aims to resolve the limitations of currently available nitrones and NOS inhibitors using a free radical-sensitive pro-drug approach. The molecules are designed based on their respective radical adduct decomposition products, which are shown to form in vivo at the site of oxidative stress, selectively targeting dysfunctional and uncoupled NOS. Applications• The molecules may be used in the treatment of ischemic stroke Advantages• There are currently no reported nitrone-NOS inhibitors. These molecules act via a combination of mechanisms unlike currently available conventional nitrones• The class of molecules proposed will allow for site-specific targeting, which may solve off-target effects exhibited by conventional NOS inhibitors IP Status: Patent Pending Publications: Nash KM et al., Development of a reactive oxygen species-sensitive nitric oxide synthase inhibitor for the treatment of ischemic stroke. Free Radical Biology & Medicine, 2017, 395-404
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