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.
Highlights
In addition to being the second leading cause of death worldwide [1], stroke is the leading cause of acquired adult disability [2]
Oxidative stress as a result of excess production of reactive oxygen species (ROS) and/or impaired metabolism is a fundamental mechanism of cell damage following cerebral ischaemia, where ROS refers to molecular oxygen
Strategies aimed at reducing oxidative stress by increasing levels of the antioxidant superoxide dismutase (SOD) in experimental models of stroke have demonstrated the integral role of ROS in lesion progression
Summary
In addition to being the second leading cause of death worldwide [1], stroke is the leading cause of acquired adult disability [2]. 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. Oxidative stress as a result of excess production of ROS and/or impaired metabolism is a fundamental mechanism of cell damage following cerebral ischaemia, where ROS refers to molecular oxygen (O2−) or its derivatives. In times of excess ROS production, such as following cerebral ischaemia/reperfusion, the balance of oxidants exceeds anti-oxidant protection. XO can oxidise the reaction of hypoxanthine to xanthine and xanthine to uric acid, producing O2− and H2O2 [26]
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