Stroke is a major cause of death and long-term disability worldwide and is associated with significant clinical and socioeconomical implications, emphasizing the need for effective therapies. In fact, current therapeutic approaches, including antiplatelet and thrombolytic drugs, only partially ameliorate the clinical outcome of stroke patients because such drugs are aimed at preserving or restoring cerebral blood flow rather than at preventing the actual mechanisms associated with neuronal cell death [1,2]. 1742-4658.2008.06766.x Neuroinflammatory mediators play a crucial role in the pathophysiology of brain ischemia, exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. Within hours after the ischemic insult, increased levels of cytokines and chemokines enhance the expression of adhesion molecules on cerebral endothelial cells, facilitating the adhesion and transendothelial migration of circulating neutrophils and monocytes. These cells may accumulate in the capillaries, further impairing cerebral blood flow, or extravasate into the brain parenchyma. Infiltrating leukocytes, as well as resident brain cells, including neurons and glia, may release pro-inflammatory mediators, such as cytokines, chemokines and oxygen ⁄ nitrogen free radicals that contribute to the evolution of tissue damage. Moreover, recent studies have highlighted the involvement of matrix metalloproteinases in the propagation and regulation of neuroinflammatory responses to ischemic brain injury. These enzymes cleave protein components of the extracellular matrix such as collagen, proteoglycan and laminin, but also process a number of cell-surface and soluble proteins, including receptors and cytokines such as interleukin-1b. The present work reviewed the role of neuroinflammatory mediators in the pathophysiology of ischemic brain damage and their potential exploitation as drug targets for the treatment of cerebral ischemia.Abbreviations BBB, blood-brain barrier; COX-2, cyclooxygenase-2; ICAM-1, intercellular adhesion molecule 1; ICE, interleukin-1b-converting enzyme; IL, interleukin; IL-1ra, interleukin-1 receptor antagonist; iNOS, inducible nitric oxide synthase; MCAO, middle cerebral artery occlusion; MCP-1, monocyte chemotactic protein-1; MMP, matrix metalloproteinase; NO, nitric oxide; TNF, tumor necrosis factor.
13The development of tissue damage after an ischemic insult occurs over time, evolving within hours or several days and is dependent on both the intensity and the duration of the flow reduction, but also on flowindependent mechanisms, especially in the peri-infarct brain regions [3].A few minutes after the onset of ischemia, tissue damage occurs in the centre of ischemic injury, where cerebral blood flow is reduced by more than 80%. In this core region, cell death rapidly develops as a consequence of the acute energy failure and loss of ionic gradients associated with permanent and anoxic depolarization [4,5]. A few hours later, the infarct expands into the pen...
