Oxidative Stress and the Use of Antioxidants in Stroke

Your doctor will need to read this all. It talks about ebselen, Normobaric oxygen, lubeluzole, nitric oxide, Mitoquinone. I sure your doctor can rattle off all the research with these compounds and why none of it can be used for your recovery. There are only 211 supporting research articles for this writeup. 

Oxidative Stress and the Use of Antioxidants in Stroke

Rachel Shirley ^†, Emily N. J. Ord ^† and Lorraine M. Work *

Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, BHF GCRC, 126 University Place, Glasgow G12 8TA, UK; E-Mails: Rachel.Shirley@glasgow.ac.uk (R.S.); Emily.Ord@glasgow.ac.uk (E.N.J.O.)

^†

These authors contributed equally to this work.

*

Author to whom correspondence should be addressed; E-Mail: Lorraine.Work@glasgow.ac.uk; Tel.: +44-141-330-5869; Fax: +44-141-330-5339.

Received: 24 February 2014; in revised form: 8 May 2014 / Accepted: 14 May 2014 /
Published: 3 July 2014

Abstract

: Transient or permanent interruption of cerebral blood flow by occlusion of a cerebral artery gives rise to an ischaemic stroke leading to irreversible damage or dysfunction to the cells within the affected tissue along with permanent or reversible neurological deficit. Extensive research has identified excitotoxicity, oxidative stress, inflammation and cell death as key contributory pathways underlying lesion progression. The cornerstone of treatment for acute ischaemic stroke remains reperfusion therapy with recombinant tissue plasminogen activator (rt-PA). The downstream sequelae of events resulting from spontaneous or pharmacological reperfusion lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous anti-oxidant protection strategies. As such, anti-oxidant therapy has long been investigated as a means to reduce the extent of injury resulting from ischaemic stroke with varying degrees of success. Here we discuss the production and source of these ROS and the various strategies employed to modulate levels. These strategies broadly attempt to inhibit ROS production or increase scavenging or degradation of ROS. While early clinical studies have failed to translate success from bench to bedside, the combination of anti-oxidants with existing thrombolytics or novel neuroprotectants may represent an avenue worthy of clinical investigation. Clearly, there is a pressing need to identify new therapeutic alternatives for the vast majority of patients who are not eligible to receive rt-PA for this debilitating and devastating disease.

Keywords:

anti-oxidant; stroke; oxidative stress

1. Introduction

In addition to being the second leading cause of death worldwide [1], stroke is also the leading cause of acquired adult disability [2]. Stroke therefore has a very large socioeconomic impact with one third of all stroke patients requiring permanent residential care, costing the NHS in the UK £3.8 billion per annum [3]. The only approved pharmacological intervention for stroke is intravenous administration of the thrombolytic, recombinant tissue plasminogen activator (rtPA), within 4.5 h of the onset of ischaemia [4]. This short therapeutic window results in only 2%–5% of all stroke patients receiving this intervention with successful reperfusion of the brain occurring in only 50% of that cohort [5], as such this is a disease with largely unmet clinical needs. Ischaemic stroke (as opposed to haemorrhagic stroke) results from an atherothrombotic or embolic blockage to a cerebral artery and accounts for ~80% of all stroke cases. Finding a new pharmacological treatment for stroke is incredibly complex for a number of reasons. The brain is a highly metabolically active organ that relies on constant oxygen and glucose supply from the circulation. The brain accounts for 2% of the total body but requires 20% O₂ and 2% of the entire body’s glucose consumption, although it performs no mechanical work or external secretory activity [6]. Storage of energy and metabolites within the brain is extremely low and as such the brain is exceptionally sensitive to interruptions in blood flow [7]. Although the brain is protected from systemic toxins under normal physiological conditions by the blood-brain barrier (BBB), this is broken down during cerebral ischaemia allowing infiltration of inflammatory mediators and other potentially toxic molecules. Following the onset of ischaemia numerous pathways contribute to brain injury, there is extensive crosstalk between these deleterious pathways with them also, in the main, existing as positive feedback loops serving to amplify insult. In what is the most significant challenge of stroke treatment, the majority of damage occurs within minutes and the acute hours following cerebral ischaemia and as such, stroke treatment at present remains mainly preventative. Here, we will discuss the source and consequence of reactive oxygen species (ROS) imbalance following cerebral ischaemia/reperfusion before considering anti-oxidant strategies attempted clinically based on the pre-clinical evidence for each. What is clear is that while the contributory role of ROS in stroke cannot be disputed, the relative merit of anti-oxidant therapy alone has yet to be established and combined therapy may be where agents modulating the balance of ROS prove beneficial.