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Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

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.

SUBMITTER: Zaidi SK

PROVIDER: S-EPMC8615482 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

Zaidi Syed Kashif SK Ahmed Farid F Alkhatabi Heba H Hoda Md Nasrul MN Al-Qahtani Muhammad M

Biomolecules 20211027 11

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 ...[more]

PMID: 34827584

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Project description:This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Project description:RationaleProtein S-nitros(yl)ation (SNO) has been implicated as an essential mediator of nitric oxide-dependent cardioprotection. Compared with males, female hearts exhibit higher baseline levels of protein SNO and associated with this, reduced susceptibility to myocardial ischemia-reperfusion injury. Female hearts also exhibit enhanced S-nitrosoglutathione reductase (GSNO-R) activity, which would typically favor decreased SNO levels as GSNO-R mediates SNO catabolism.ObjectiveBecause female hearts exhibit higher SNO levels, we hypothesized that GSNO-R is an essential component of sex-dependent cardioprotection in females.Methods and resultsMale and female wild-type mouse hearts were subjected to ex vivo ischemia-reperfusion injury with or without GSNO-R inhibition (N6022). Control female hearts exhibited enhanced functional recovery and decreased infarct size versus control males. Interestingly, GSNO-R inhibition reversed this sex disparity, significantly reducing injury in male hearts, and exacerbating injury in females. Similar results were obtained with male and female GSNO-R-/- hearts using ex vivo and in vivo models of ischemia-reperfusion injury. Assessment of SNO levels using SNO-resin assisted capture revealed an increase in total SNO levels with GSNO-R inhibition in males, whereas total SNO levels remained unchanged in females. However, we found that although GSNO-R inhibition significantly increased SNO at the cardioprotective Cys39 residue of nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 3 in males, SNO-NADH dehydrogenase subunit 3 levels were surprisingly reduced in N6022-treated female hearts. Because GSNO-R also acts as a formaldehyde dehydrogenase, we examined postischemic formaldehyde levels and found that they were nearly 2-fold higher in N6022-treated female hearts compared with nontreated hearts. Importantly, the mitochondrial aldehyde dehydrogenase 2 activator, Alda-1, rescued the phenotype in GSNO-R-/- female hearts, significantly reducing infarct size.ConclusionsThese striking findings point to GSNO-R as a critical sex-dependent mediator of myocardial protein SNO and formaldehyde levels and further suggest that different therapeutic strategies may be required to combat ischemic heart disease in males and females.

Project description:BackgroundIntraventricular hemorrhage (IVH) is often caused by irruption of intracerebral hemorrhage (ICH) of basal ganglia or thalamus into the ventricular system. Instillation of recombinant tissue plasminogen activator (rtPA) via an external ventricular drainage (EVD) has been shown to effectively decrease IVH volumes while the impact of rtPA instillation on ICH volumes remains unclear. In this series, we analyzed volumetric changes of ICH in patients with and without intrathecal lysis therapy.MethodsBetween 01/2013 and 01/2019, 36 patients with IVH caused by hemorrhage of basal ganglia, thalamus or brain stem were treated with rtPA via an EVD (Group A). Initial volumes were determined in the first available computed tomography (CT) scan, final volumes in the last CT scan before discharge. During the same period, 41 patients with ICH without relevant IVH were treated without intrathecal lysis therapy at our neurocritical care unit (Group B). Serial CT scans were evaluated separately for changes in ICH volumes for both cohorts using OsiriX DICOM viewer. The Wilcoxon signed-rank test was performed for statistical analysis in not normally distributed variables.ResultsMedian initial volume of ICH for treatment Group A was 6.5 ml and was reduced to 5.0 ml after first instillation of rtPA (p < 0.01). Twenty-six patients received a second treatment with rtPA (ICH volume reduction 4.5 to 3.3 ml, p < 0.01) and of this cohort further 16 patients underwent a third treatment (ICH volume reduction 3.0 ml to 1.5 ml, p < 0.01). Comparison of first and last CT scan in Group A confirmed an overall median percentage reduction of 91.7% (n = 36, p < 0.01) of ICH volumes and hematoma resolution in Group A was significantly more effective compared to non-rtPA group, Group B (percentage reduction = 68%) independent of initial hematoma volume in the regression analysis (p = 0.07, mean 11.1, 95%CI 7.7-14.5). There were no adverse events in Group A related to rtPA instillation.ConclusionIntrathecal lysis therapy leads to a significant reduction in the intraparenchymal hematoma volume with faster clot resolution compared to the spontaneous hematoma resorption. Furthermore, intrathecal rtPA application had no adverse effect on ICH volume.

Project description:Background and aimsFunctional outcome following mechanical thrombectomy (MT) in patients with acute ischemic stroke and large vessel occlusion is time-dependent and worsens with increasing delay. Time to endovascular reperfusion is potentially modifiable with changes in organizational structure. We investigated the changes in time to reperfusion of relocating the intravenous thrombolysis (IVT) services from a non-MT center to a MT-capable center.MethodsWe present an observational, consecutive, retrospective, single-center cohort study of 253 stroke patients treated with MT, 2017-2019. The observation period was divided into before and after the relocation of IVT services in 2018, period 1 and period 2, respectively. The two hospitals were located 13 km apart in an urban area, and following the relocation, IVT was administered at the MT-capable center. Time metrics were registered and divided into two main intervals, namely, ambulance departure from stroke onset location to imaging (ambulance-imaging) and imaging to reperfusion (imaging-reperfusion). The interval imaging-reperfusion included inter-hospital transfer to the MT-capable center in period 1. The association of the imaging-reperfusion duration and functional outcome at 90 days was analyzed using ordinal logistic regression.ResultsNo significant change in ambulance-imaging was observed from a median of 27 min (interquartile range [IQR] 22-37) in period 1 to 30 min (IQR 23-40) in period 2, p = 0.19, while the median time of imaging-reperfusion decreased from 173 min (IQR 137-230) to 114 min (IQR 84-152), p < 0.001. The largest absolute time reduction from imaging to reperfusion was seen from imaging to arrival at the angio suite from 89 min (IQR 76-111) to 42 min (IQR 28-63), p < 0.001, which included inter-hospital transfer in period 1. In multivariate analysis, every 10 min of increased delay from imaging to reperfusion was associated with poorer functional outcome with an adjusted odds ratio of 0.95 (95% CI: 0.95-0.98), p < 0.001.ConclusionRelocation of IVT services to an MT-capable center was the main cause of reduced time to reperfusion for patients treated with MT and was implemented without affecting prehospital transportation time. These results suggest that patient outcome can be improved by optimizing the organization of IVT and MT services in urban areas.

Dataset Information

Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

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Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage.

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