Abstract
Background: This project aims to evaluate the potential beneficial effects of a selective S-nitrosoglutathione reductase (GSNOR) inhibitor on post-acute stroke outcomes. Nitric oxide (NO) metabolome plays a critical role in stroke towards maintaining the crucial levels of deleterious peroxynitrite (ONOOO - ) vs. beneficial S-nitrosoglutahione (GSNO). The homeostasis of endogenously-produced-GSNO following stroke is altered due to aberrantly increased activity of GSNO-degrading enzyme GSNOR. GSNO’s role in the context of stroke is recognized as anti-inflammatory, neuroprotective and neurorestorative. Therefore, we investigated the efficacy of a new and orally bioavailable GSNOR inhibitor N91115 (cavosonstat) in a mouse model of transient cerebral ischemia and reperfusion (IR). Methods: To determine the neuroprotective efficacy of GSNOR, a wild-type mouse model of middle cerebral artery occlusion (60 min) and reperfusion was used. N91115 (1 mg/kg body weight) was administered orally initially at 2 h after the reperfusion and the same treatment dose was repeated once a day for 3 consecutive days. The animals were evaluated for brain infarctions, neurological deficits, nitroxidative stress and the activity/expression of GSNOR. The study was validated in a GSNOR knock-out (KO) mouse model of IR. Results: The post-injury treatment with N91115 reduced brain infarctions and edema and improved survival and functional outcomes. The treatment also decreased the IR-induced GSNOR activity and the levels of injurious peroxynitrite. The significance of GSNOR inhibition-based mechanisms in neuroprotection was supported by a GSNOR KO mice study, showing significantly reduced brain infarctions and decreased neurological deficits following stroke. Conclusion: The study shows the neuroprotective and functional recovery potential of orally administered N91115 through the inhibition of GSNOR. Based on the safety profile in humans, favorable pharmacokinetics and neuroprotective efficacy in an animal model of stroke, N91115 seems to be an ideal small molecule drug to be investigated in stroke patients.
Published Version
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