Abstract
The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of “clinically” relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, “IV-effects” of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 μg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.
Highlights
Stroke primarily happens due to a thromboembolic occlusion (~87% strokes) resulting in reduced cerebral blood flow (CBF) and decreased brain tissue oxygenation (PbtO2) [1].More than 13 million strokes per year occur worldwide, placing stroke among the leading causes of adult mortality and disability [2]
A higher dose of IV‐GSNO at 1 mg/kgbwt significantly lowered whether a change in the route of administration of GSNO will abolish its blood pressure (BP)-lowering the BP as compared to the baseline control (p < 0.0001; Figure 1A); a low‐dose effect
To the best our knowledge, this is the first report demonstrating the efficacy of GSNO, an endogenous major carrier/donor of report
Summary
Stroke primarily happens due to a thromboembolic occlusion (~87% strokes) resulting in reduced cerebral blood flow (CBF) and decreased brain tissue oxygenation (PbtO2) [1].More than 13 million strokes per year occur worldwide, placing stroke among the leading causes of adult mortality and disability (http://world-stroke.org, accessed on 31 August2021) [2]. Stroke primarily happens due to a thromboembolic occlusion (~87% strokes) resulting in reduced cerebral blood flow (CBF) and decreased brain tissue oxygenation (PbtO2) [1]. More than 13 million strokes per year occur worldwide, placing stroke among the leading causes of adult mortality and disability Advancements in stroke management made faster interventions feasible in remote settings, thereby reducing the mortality but the risk of increasing number of disabled survivors remains associated [3]. Since the microvascular reperfusion and restoration of PbtO2 remains the only proven therapeutic strategy in stroke, the development of field therapies, which can be conveniently administered to the stroke victims in the primary care centers, during transportation and in the emergency departments (EDs), is essentially needed. Biomolecules 2021, 11, 1587 for faster interventions. The development of adjunct therapies which will not contradict with the FDA-approved reperfusion therapies but will enhance benefits of reperfusion, is highly encouraged [4]
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