Serial Review: Free Radicals and StrokeOxidative stress during the chronic phase after stroke☆
Introduction
Stroke is a leading cause of death and long-term disability in industrialized countries. The main priority of basic and clinical sciences is the search for effective treatment of stroke patients. The numerous investigations published so far show that stroke is a disease susceptible to treatment in the hyperacute phase but its effectiveness is rather limited [1]. They provide optimism for development of new therapies aiming to improve the functional outcome of patients and their recovery. On the other hand, the opportunities for therapy during the subacute and chronic stages of stroke should not be ignored. Survivors of stroke are at a high risk of subsequent vascular complications and new vascular accidents. It is a problem of significant social and economic consequences since nowadays there are over 50 million stroke survivors alive in the world. That is why the efforts in stroke patients should be directed to both the stimulation of neurological recovery mechanisms and a reduction in the probability of appearance of subsequent cerebrovascular events.
In recent years, the identification of a number of molecules contributing to the neuronal death, particularly apoptosis, has thrown light on the pathogenesis of brain damage after ischemic and hemorrhagic stroke. Oxidative stress is believed to be one of the mechanisms taking part in the neuronal damage of stroke.
Oxidative stress is a state of imbalance between free radical production, in particular, reactive oxygen species (ROS), and the ability of the organism to defend against them, leading to progressive oxidative damage. The study of oxidative stress in stroke is difficult to conduct because of the complexity of ongoing processes, each of which may cause radical overproduction and oxidative damage, as well as because of the complicated interaction between these processes due to the presence of direct and reverse relations, some of which may exacerbate or reduce the degree of damage. It is assumed that oxidative stress contributes to the initiation and development of stroke via different interrelated mechanisms: excitotoxicity resulting in cellular enzyme activation and ROS generation; inflammation leading to leukocyte priming and activation and accompanied by an excessive radical production; activation and oxidative damage of endothelium resulting in reduced bioavailability of nitric oxide (NO·); free radical-mediated hyperhomocysteinemia; lipid peroxidation of plasma and cellular components including those in the arterial vessel wall and macrophages, processes each one of which may exacerbate oxidative damage through mechanisms of positive feedback.
There is ample evidence from experimental models for enhanced free radical generation in the brain during cerebral ischemia/reperfusion. Direct clinical studies verifying the relation between stroke and oxidative stress are yet missing mainly because of morphological difficulties arising when measuring free radicals in cerebral tissue. ROS are short-living compounds. Nevertheless, they initiate complex chain reactions that produce a range of molecular structures, many of which are yet unknown. The elevation in lipid peroxidation products in the circulation and the weakened cellular antioxidant defense system are considered an indirect proof of oxidative stress arising in stroke. New and reliable markers for oxidative stress are still being sought by scientists in their research work [2].
Studies monitoring the changes in the oxidative stress indicators during the chronic phase after stroke are scarce. The interpretation of results obtained in chronic stroke patients is getting more complicated by the fact that stroke is an etiologically and pathologically heterogeneous disease and the risk factors for a given type of stroke may not be risk factors for another stroke subtype. Risk factors bring about a chronic change in the walls of blood vessels that include additional activation of inflammatory and free radical mechanisms. Approximately one-fifth of stroke patients have diabetes mellitus, a considerable amount of them have high blood pressure, and some of them have or have had a recent infection or inflammation. Furthermore, in the presence of more than one risk factor, their combined influence on the free radical processes should also be taken into consideration, as it may be an additive or synergistic one. Thus, the vascular risk factors may cooperatively increase the risk of subsequent stroke.
This review presents the current state of knowledge on the potential role of oxidative stress during the chronic phase after stroke. On the basis of the pathophysiological changes observed in stroke survivors, a hypothesis on the contribution of oxidative stress to the development of processes preventing the recovery of the patients and exacerbating their vascular complications has been established. The role of various oxidative stress markers in the development of the processes leading to the appearance of new vascular events has been discussed as well.
Section snippets
Inflammation—A source of oxidative stress in the chronic phase after stroke
Inflammation participates in the mechanisms of cerebral injury and recovery after stroke, but at the same time it is a risk factor for stroke [3], [4]. Inflammation in stroke is mediated by both molecular components, particularly cytokines, chemokines, and growth factors, and cellular components, such as leukocytes and microglia, many of which having anti- or proinflammatory properties with beneficial or deleterious effects [5], [6]. Inflammation is accompanied by mobilization and activation of
Homocysteinemia—A marker of oxidative stress in the chronic phase after stroke
A number of mechanisms have been proposed in the literature to explain the influence of the increased level of plasma sulfhydryl amino acid homocysteine on blood vessels and stroke-endothelial dysfunction, oxidation of LDL, increased monocyte adhesion to the vessel walls, impaired vascular response to NO· (reduced production of NO·), increased ROS generation, and a tendency to thrombus formation, mediated by the activation of coagulation factors and platelet dysfunction. A significant platelet
Antioxidant defense system
The data published on the status of the antioxidant defense system in the convalescent phase of stroke are scarce. In our laboratory, we did not find any change in erythrocyte superoxide dismutase (SOD) activity, blood catalase (CTS), and glutathione peroxidase (GSH-Px) activities and the level of SH groups in blood in the convalescent stage of stroke [29]. Most probably, for chronic stroke patients, it would be better to measure the levels of the extracellular antioxidants, in particular the
Products of oxidative damage
Since most free radicals are extremely reactive and have a short-life time, it is difficult for them to be measured directly. In most studies, indirect approaches have been used to demonstrate free radical production in stroke. Products of the reactions of free radicals with other molecules, such as deoxyribonucleic acid (DNA), lipids, and proteins have been determined [73].
Few studies address the level of lipoproxidation products in the chronic stage after stroke. In our laboratory, we found
Possible therapeutic strategies with antioxidants in acute and convalescent phases after stroke
Over recent years, remarkable success has been achieved in elucidating the mechanisms that contribute to ischemic brain injury but an effective treatment protecting brain tissue from the complex neurochemical cascade has not been discovered [77].
There is compelling evidence for the role of oxidative stress in the destructive consequences of stroke. Recent evidence has pointed out that ROS generation after stroke is a long-lasting process [78]. The by-products of lipid peroxidation are also
Concluding remarks
An important task of stroke research is to provide opportunities for improving neurological recovery and clinical outcome of patients. Only about half of stroke survivors are independent 6 months after stroke. Further, subjects with a history of stroke are at an increased risk of subsequent vascular events, a problem of significant social and economic consequences. Data collected from clinical trials in acute and chronic stroke provide evidence that a incidence and high mortality of
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This article is part of a series of reviews on Free Radicals and Stroke. The full list of papers may be found on the home page of the journal.