Do Concentration or Activity of Selenoproteins Change in Acute Stroke Patients? A Systematic Review and Meta-Analyses

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Do Concentration or Activity of Selenoproteins Change in Acute Stroke Patients? A Systematic Review and Meta-Analyses

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Sabrina Tamburranoa, b Sarah Rhodesc
 Ioana-Emilia Mosneaga, d
Lucy Robertsa, d Madeleine E.D. Hurrya, d, e John R. Graingerb, e
Tovah N. Shawf
 Craig J. Smitha, e, g Stuart M. Allana, d, e
a
Geoffrey Jefferson Brain Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health
Science Centre, University of Manchester, Manchester, UK; bDivision of Infection, Immunity and Respiratory
Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester,
Manchester, UK; c
Centre for Biostatistics, Division of Population Health, Health Services Research & Primary Care,
School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK;
dDivision of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine
and Health, University of Manchester, Manchester, UK; eLydia Becker Institute of Immunology and Inflammation,
Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester,
Manchester, UK; f
Institute of Immunology and Infection Research, School of Biological Sciences, University of
Edinburgh, Ashworth Laboratories, Edinburgh, UK; gManchester Centre for Clinical Neurosciences, Salford Royal
NHS Foundation Trust, Salford, UK

Abstract

Introduction: 

 

Stroke is characterized by deleterious oxidative stress. Selenoprotein enzymes are essential endogenous antioxidants, and detailed insight into their role after
stroke could define new therapeutic treatments. This systematic review aimed to elucidate how blood selenoprotein
concentration and activity change in the acute phase of
stroke. 

Methods: 

We searched PubMed, EMBASE, and Medline databases for studies measuring serial blood selenoprotein concentration or activity in acute stroke patients or in
stroke patients compared to non-stroke controls. Metaanalyses of studies stratified by the type of stroke, blood
compartment, and type of selenoprotein measurement
were conducted. 

 

Results: 

 

Eighteen studies and data from 941 stroke patients and 708 non-stroke controls were included in this review. Glutathione peroxidase (GPx) was the only identified selenoprotein, and its activity was most frequently measured. Results from 12 studies and 693 patients showed that compared to non-stroke controls in acute ischaemic stroke patients, the GPx activity increased in haemolysate (standardized mean difference [SMD]: 0.27, 95% CI: 0.07–0.47) but decreased in plasma (mean difference
[MD]: −1.08 U/L, 95% CI: −1.94 to −0.22) and serum (SMD: −0.54, 95% CI: −0.91 to −0.17). From 4 identified studies in 106 acute haemorrhagic stroke patients, the GPx activity decreased in haemolysate (SMD: −0.40, 95% CI: −0.68 to −0.13) and remained unchanged in plasma (MD: −0.10 U/L, 95% CI:
−0.81 to 0.61) and serum (MD: −5.00 U/mL, 95% CI: −36.17 to 26.17) compared to non-stroke controls. Results from studies assessing the GPx activity in the haemolysate compartment were inconsistent and characterized by high heterogeneity. Conclusions: Our results suggest a reduction of the blood GPx activity in acute ischaemic stroke patients, a lack of evidence regarding a role for GPx in haemorrhagic stroke patients, and insufficient evidence for other selenoproteins.

Introduction

The use of antioxidant therapies is a promising direction for the development of new treatments for stroke. Oxidative stress is a common feature of ischaemic and haemorrhagic stroke [1], and several preclinical studies [2–5] have demonstrated that an increase in antioxidant enzymes could be protective against stroke. Since oxidative stress is a key factor in the pathophysiology of stroke and could be used to develop novel therapies, further understanding of endogenous antioxidant mechanisms occurring after stroke is crucial. Some selenium-dependent proteins, or selenoproteins, are key elements in the endogenous antioxidant system. One of the most important selenoprotein enzymes included in the first line of antioxidant defence is glutathione peroxidase (GPx), which functions to neutralize hydrogen peroxide (H2O2) generated by the dismutation of superoxide anions [6]. H2O2 can easily cross cell membranes, leading to wide-spread oxidative stress-induced damage during stroke [7]. As an H2O2 scavenger, GPx may be able to interrupt this detrimental oxidative stress propagation in the brain. In agreement with a potential protective role for GPx in stroke, polymorphisms causing a reduction in its transcriptional activity are associated with increased risk of ischaemic stroke and thrombosis [8–10]. Furthermore, in addition to increasing the transcription of several selenoprotein genes in the brain, intraperitoneal injection of selenium-containing peptides in a mouse model of intracerebral haemorrhage (ICH) results in the reduction of oxidative stress, excitotoxicity, and consequently haematoma volume [3]. One of the most promising antioxidant clinical trials in stroke concerned the use of ebselen, a seleno-organic compound with mimetic antioxidant activity to GPx. Oral administration of ebselen improved neurological deficits and reduced ischaemic volume in rodent models of focal cerebral ischaemia but, in clinical trials, showed beneficial effects only until 1 month post-stroke [5, 11].
To date, the precise role of selenoproteins in the aetiology and pathophysiology of stroke is still controversial. In this study, we aimed to clarify how selenoprotein concentration and activity change in the acute phase of stroke by undertaking a systematic review and meta-analysis of observational clinical studies.