Investigation of S-Nitrosoglutathione in stroke: A systematic review and meta-analysis of literature in pre-clinical and clinical research

Abstract

Background

S-Nitrosoglutathione (GSNO) is a nitric oxide donor that has been investigated for neuroprotective and neuro-recovery effect. We aimed to conduct a systematic review on the published literatures using GSNO in both pre-clinical and clinical stroke studies.

Methods

We searched PubMed up to June 30, 2019, using the following keywords: S-Nitrosoglutathione, GSNO, stroke, cerebrovascular, carotid arteries, middle cerebral artery, and middle cerebral artery occlusion. Only studies published in the English language providing efficacy results of GSNO on ischemic stroke were included. Stroke Therapy Academic Industry Roundtable (STAIR) score was used to assess the quality of pre-clinical studies and PEDro score for clinical trials. A meta-analysis was conducted to compare the effect size.

Results

Of 39 articles identified, 10 (6 for pre-clinical and 4 for clinical studies) met the eligibility criteria and were included. The median STAIR score across the pre-clinical studies was 5.5 (range: 4–7), and the median PEDro score for the 4 clinical trials was 10 (ranged: 6 to 10). Among the 6 pre-clinical studies, GSNO reduced infarct size in 6 studies and improved neurological behavior scales in 5 studies compared to placebo. Inverse-variance weighted linear meta-analysis of standardized mean difference (Hedge's g) on 4 human studies revealed a big effect size (Hedge's g = −0.82, 95% CI: [−1.26, −0.38], P = .0003) favoring the GSNO group in term of reducing embolic signals. I² value was 0 across the included clinical studies in the meta-analysis.

Conclusions

Pre-clinical studies showed positive benefit of GSNO in animal stroke models. The meta-analysis of clinical studies demonstrated that GSNO is effective in reducing embolic signals in patients with symptomatic internal carotid artery stenosis undergoing carotid endarterectomy or stenting. Further investigation of this molecule is warranted.

Introduction

Stroke is one of the leading causes of morbidity and mortality globally (Benjamin et al., 2018). Early recanalization therapy through intravenous thrombolysis and/or mechanical thrombectomy is the crucial part in the early management of ischemic stroke (Powers et al., 2018). Despite the high rate of successful recanalization, there is only approximately 50% rate of functional independence at 90 days post-stroke (Davalos et al., 2017). Seeking effective neuroprotectant remains critical in the acute ischemic stroke treatment. While pre-clinical data showed the promising efficacy of numerous neuroprotective molecules in ischemic stroke, clinical trials have not been successful in translating these agents into bedside.

S-nitrosoglutathione (GSNO),¹ an endogenous low molecular weight S-nitrosothiol formed by nitrosation of reduced glutathione, is a natural component of the human body existing in the brain and other organs (Kluge et al., 1997; Singh et al., 1996). GSNO is involved in storing and transporting of nitric oxide (NO)² (Khan et al., 2015a), which is a key signaling molecule in regulating cerebral blood flow, and the NO derived from endothelial nitric oxide synthase were shown to have neuroprotective effects (Garry et al., 2015). GSNO protects the ischemia/ reperfusion injury against inflammation and neuron cell death by modulating the NO system (Khan et al., 2005). GSNO has the effect of systemic vasorelaxation (Rassaf et al., 2002), which may be related with the inhibition of platelet functions (de Belder et al., 1994; Gordge and Xiao, 2010; Salas et al., 1998). GSNO also showed the protective effect of blood-brain barrier and epithelia permeability (Khan et al., 2009; Savidge et al., 2007). Exogenous administration of GSNO may have the potential of stimulating neuroregeneration via the stabilization of the HIF-1α/VEGF pathway in the chronic phase of stroke disease (Khan et al., 2015a). Prior studies indicated GSNO was effective in improving neurological functional recovery in animal models of ischemia (Sakakima et al., 2012), traumatic brain injury (Khan et al., 2009; Khan et al., 2011) and subarachnoid hemorrhage (Sehba et al., 1999). GSNO has been applied in human both in healthy condition and vascular disease conditions including stroke.

Before planning costly clinical trial using GSNO, it is an important step to conduct a critical appraisal of the published literatures in both pre-clinical and clinical studies on this topic to identify potential gaps and issues. Therefore, we aimed to conduct both qualitative (systematic review) and quantitative (meta-analysis) review on the investigation GSNO in stroke.