The treatment of ischemic stroke (IS) remains a big challenge in clinics, and it is urgently needed to develop novel, safe, and effective medicines against IS. Here, we report the design, synthesis, and biological evaluation of organic NO donors as potential agents for the treatment of IS. The representative compound was able to slowly generate low concentrations of NO by reaction with a thiol-containing nucleophile, and the NO was selectively converted into NO under ischemic/hypoxia conditions to protect primary rat neurons from oxygen-glucose deprivation and recovery (OGD/R)-induced cytotoxicity by enhancing the Nrf2 signaling and activating the NO/cGMP/PKG pathway. Treatment with at 2 h before or after ischemia mitigated the ischemia/reperfusion-induced brain injury in middle cerebral artery occlusion (MCAO) rats by producing NO and enhancing Nrf2 signaling. Furthermore, significantly promoted endothelial cell proliferation and angiogenesis within the ischemic penumbra. Our findings suggest that this type of NO donors, like , may be valuable to fight IS and other ischemic diseases.
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