Molecular Pathophysiology of Stroke

Cerebral ischemia occurs when the amount of oxygen and other nutrients supplied by blood flow is insufficient to meet the metabolic demands of brain tissue. In ischemic stroke, the blood supply to the brain is disrupted by cerebrovascular disease. For decades, extensive research and clinical approaches to combat stroke have focused on the vascular aspects of cerebral ischemia. Therapeutic advances, including carotid endarterectomy, thrombolytic therapy, anticoagulation for cardiogenic stroke, antiplatelet agents, and the treatment of risk factors such as hypertension and hyperlipemia, have had significant effects on the morbidity and mortality of stroke. The final event in cerebral ischemia is the death of neurons, resulting in irreversible loss of neurologic function. The advent of animal and tissue culture models of ischemia has led to many new insights into the mechanisms by which ischemic neurons die. If ischemia is complete and prolonged, neuronal death is inevitable. However, it has become increasingly clear that many secondary biochemical changes that exacerbate injury occur in response to the initial insult. In models of cerebral ischemia in rodents, as much as 50% or more of ischemic brain may be spared from infarction by preventing these secondary biochemical events. Understanding of the mechanisms by which neuronal cell death takes place has resulted in a number of therapeutic strategies that aim to prevent secondary biochemical changes and thus decrease the damage that results from cerebral ischemia. These basic mechanisms may also have relevance to other neurodegenerative diseases associated with excessive neuronal death. This chapter summarizes many of the mechanisms that have been demonstrated to exacerbate the neuronal death caused by hypoxia and hypoglycemia. Ischemic neuronal death may involve the activation of enzymes and receptors