Neuroinflammation and Immune Regulation in Ischemic Stroke: Identification of New Pharmacological Targets

Stroke is among the most common diseases of advanced age and is becoming a steadily increasing fi nancial healthcare problem in the industrialized world with the increasing longevity and aging of the population. The incidence of ischemic stroke is highest in the elderly population, representing one of the most common causes of disability and mortality worldwide. Over the past decades, a tremendous amount of research has been undertaken into developing effective therapeutic strategies for the treatment of acute stroke. Unfortunately, many neuroprotective agents that have shown successful results in treating animal models of acute stroke have failed to translate into clinical treatments. Only tissue plasminogen activator is currently licensed for use in the treatment of acute ischemic stroke. Increasing evidence shows that the central nervous system and the immune system interact in complex ways, and better insight into these interactions may be relevant to the treatment of patients with stroke and other forms of central nervous system injury. However, during recent years, promising fi ndings suggest that systemic infl ammation and neuroinfl ammation are central features in cerebrovascular disease. Atherosclerosis, autoimmune disease, and physiological stressors, such as infection or surgery, may be a risk factor for the initial development of cerebral ischemia. In addition, the immune system actively participates in the pathophysiological processes occurring during an ischemic stroke. Thrombosis and hypoxia trigger an intravascular infl ammatory cascade which elicits an infl ammatory response in the injured brain that is accompanied by a marked local infl ammatory reaction that is initiated by ischemiaor hematoma-induced expression of cytokines, adhesion molecules, and other infl ammatory mediators, including prostanoids, extracellular proteases, reactive oxygen species, and nitric oxide, leading to the accumulation of infl ammatory cells, such as leukocytes and microglia, which is further augmented by the innate immune response to cellular damage occurring in the parenchyma. Many of these compounds are known to promote and sustain infl ammatory responses at local and systemic level, producing a neuroinfl ammatory response and a systemic acute-phase response. The acute-phase infl ammatory response after stroke is a refl ection of an unspecifi c systemic infl ammatory response syndrome. Classic acute-phase reactants and body temperature are also modifi ed in stroke and may be useful in the prediction of events and outcome and as therapeutic targets. The activation of innate immunity after stroke sets the stage for an adaptive immune response directed against brain antigens. The pathogenic signifi cance of adaptive immunity and its long-term effects on the postischemic brain remains unclear, but it cannot be ruled out that a persistent autoimmune response to brain antigens has deleterious and long-lasting consequences, such as the development of poststroke dementia. This immune activation causes secondary tissue injury, but it is unclear whether modulating the acute immune response to stroke can produce clinical benefi ts. Better understanding of the role of the postischemic-induced infl ammatory response and its potential for modulation might have profound implications for patient treatment. Preclinical studies suggest that interventions that are aimed at attenuating such infl ammation reduce the progression of brain damage that occurs during the late stages of cerebral ischemia. In particular, strategies that block the activity of infl ammation- related enzymes reduce ischemic damage with an extended therapeutic window. Although, clinical trials using anti-infl ammatory strategies did not show benefi t in patients with ischemic stroke, there is a strong rationale for continuing to explore the effi cacy of anti-infl ammatory therapies in the treatment of the late stages of cerebral ischemia acting more on the modulation of these later events than targeting of specifi c steps in the ischemic cascade.