Serial Review: Free Radicals and Stroke
Oxidative stress during the chronic phase after stroke

https://doi.org/10.1016/j.freeradbiomed.2005.04.017Get rights and content

Abstract

Stroke is a complex disease originating and developing on the background of genetic predisposition and interaction between different risk factors that chronically damage blood vessels. The search for an effective treatment of stroke patients is the main priority of basic and clinical sciences. The chronic phase of stroke provides possibilities for therapy directed toward stimulation of recovery processes as well as prophylaxis, which reduces the probability of subsequent cerebrovascular events. Oxidative stress is a potential contributor to the pathophysiological consequences of stroke. The aim of the present review is to summarize the current knowledge of the role of oxidative stress during the chronic phase after stroke and its contribution to the initiation of subsequent stroke. The relationship among inflammation, hemostatic abnormalities, and platelet activation in chronic stroke patients is discussed in the context of ongoing free radical processes and oxidative damage. Free radical-mediated effects of increased plasma level of homocysteine and its possible contribution to the processes leading to recurrent stroke are discussed as well. The status of the antioxidant defense system and the degree of oxidative damage in the circulation of stroke survivors are examined. The results are interpreted in view of the effects of the vascular risk factors for stroke that include additional activation of inflammatory and free radical mechanisms. Also, the possibilities for combined therapy including antioxidants in the acute and convalescent stages of stroke are considered. Future investigations are expected to elucidate the role of free radical processes in the chronic phase after stroke and to evaluate the prophylactic and therapeutic potential of anti-radical agents.

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

References (128)

  • R.W. Powers et al.

    Plasma homocysteine and malondialdehyde are correlated in an age- and gender-specific manner

    Metabolism

    (2002)
  • C. Bonithon-Kopp et al.

    Combined effects of lipid peroxidation and antioxidant status on carotid atherosclerosis in a population aged 59–71 y: The EVA study

    Am. J. Clin. Nutr.

    (1997)
  • K. Yagi

    Lipid peroxides and human diseases

    Chem. Phys. Lipids

    (1987)
  • S.O. Kim et al.

    KR-31378 protects neurons from ischemia-reperfusion brain injury by attenuating lipid peroxidation and glutathione loss

    Eur. J. Pharmacol.

    (2004)
  • P.A. Li et al.

    Cyclosporin A enhances survival, ameliorates brain damage, and prevents secondary mitochondrial dysfunction after a 30-minute period of transient cerebral ischemia

    Exp. Neurol.

    (2000)
  • A. Nakano et al.

    Ischemic preconditioning: from basic mechanisms to clinical applications

    Pharmacol. Ther.

    (2000)
  • J.G. Shake et al.

    Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection

    Ann. Thorac. Surg.

    (2001)
  • U. Dirnagl et al.

    Ischemic tolerance and endogenous neuroprotection

    Trends Neurosci.

    (2003)
  • M.J. O'Neill et al.

    ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

    Brain Res.

    (2000)
  • R. Hattori et al.

    Preferential inhibition of inducible nitric oxide synthase by ebselen

    Eur. J. Pharmacol.

    (1994)
  • C. Schewe et al.

    Strong inhibition of mammalian lipoxygenases by the antiinflammatory seleno-organic compound ebselen in the absence of glutathione

    Biochem. Pharmacol.

    (1994)
  • I.A. Cotgreave et al.

    Studies on the anti-inflammatory activity of ebselen: ebselen interferes with granulocyte oxidative burst by dual inhibition of NADPH oxidase and protein kinase C?

    Biochem. Pharmacol.

    (1989)
  • H. Sheng et al.

    Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia

    Free Radic. Biol. Med.

    (2002)
  • A.J. Grau et al.

    Leukocyte count as an independent predictor of recurrent ischemic events

    Stroke

    (2004)
  • P.J. Lindsberg et al.

    Inflammation and infections as risk factors for ischemic stroke

    Stroke

    (2003)
  • G. Del Zoppo et al.

    Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia

    Brain. Pathol.

    (2000)
  • N.B. Beamer et al.

    Persistent inflammatory response in stroke survivors

    Neurology

    (1998)
  • E.S. Ford et al.

    Serum C-reactive protein and self-reported stroke: findings from the Third National Health and Nutrition Examination Survey

    Arterioscler. Thromb. Vasc. Biol.

    (2000)
  • M. Di Napoli et al.

    C-reactive protein in ischemic stroke

    Stroke

    (2001)
  • N.S. Rost et al.

    Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study

    Stroke

    (2001)
  • J. Torzewski et al.

    C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries

    Arterioscler. Thromb. Vasc. Biol.

    (1998)
  • E. Haapaniemi et al.

    Serial changes in fibrinolysis and coagulation activation markers in acute and convalescent phase of ischemic stroke

    Acta Neurol. Scand.

    (2004)
  • M. Soncini et al.

    Prognostic significance of markers of thrombin generation in the acute and chronic phases of non cardioembolic ischemic stroke

    Minerva Cardioangiol.

    (2000)
  • Y. Seki et al.

    Sustained activation of blood coagulation in patients with cerebral thrombosis

    Am. J. Hematol.

    (1995)
  • H. Tohgi et al.

    Coagulation-fibrinolysis abnormalities in acute and chronic phases of cerebral thrombosis and embolism

    Stroke

    (1990)
  • F. Van Kooten et al.

    Increased platelet activation in the chronic phase after cerebral ischemia and intracerebral hemorrhage

    Stroke

    (1999)
  • N. Vila et al.

    Proinflammatory cytokines and early neurological worsening in ischemic stroke

    Stroke

    (2000)
  • E. Van Exel et al.

    Inflammation and stroke

    Stroke

    (2002)
  • A. Flex et al.

    Proinflammatory genetic profiles in subjects with history of ischemic stroke

    Stroke

    (2004)
  • A.M. Elneihoum et al.

    Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases

    Stroke

    (1996)
  • M.L. Alexandrova et al.

    Changes in phagocyte activity in patients with ischaemic stroke

    Luminescence

    (2001)
  • D.J. McCabe et al.

    Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack

    Br. J. Haematol.

    (2004)
  • M.L. Alexandrova et al.

    Oxidative stress in the chronic phase after stroke

    Redox Rep.

    (2003)
  • I. Vermes et al.

    Altered leukocyte rheology in patients with chronic cerebrovascular disease

    Stroke

    (1988)
  • L. Szapary et al.

    Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease

    Orv. Hetil.

    (2003)
  • J.R. Hatherill et al.

    Mechanisms of oxidant-induced changes in erythrocytes

    Agents Actions

    (1991)
  • E. Ernst et al.

    Blood rheology in patients with transient ischemic attacks

    Stroke

    (1988)
  • T. Iwamoto et al.

    Platelet activation in the cerebral circulation in different subtypes of ischemic stroke and binswanger's disease

    Stroke

    (1995)
  • J.C. Grotta et al.

    Is preventing microemboli enough?

    Circulation

    (2001)
  • L.P. Rohde et al.

    Cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men

    Arterioscler. Thromb. Vasc. Biol.

    (1999)
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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.

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