Mechanisms, challenges and opportunities in stroke.

NATURE REVIEWS | NEUROSCIENCE VOLUME 4 | MAY 2003 | 399 Stroke, a brain attack, is the third leading cause of death in the Western world. Worldwide, about 5.5 million people died from stroke in 1999 — approximately 10% of all deaths. There are more than 3.5 million survivors in the United States alone, and the disease remains a major cause of disability. In practice,‘stroke’ refers to an umbrella of conditions caused by the occlusion or haemorrhage of blood vessels supplying the brain. Most often, blood flow is compromised within the territory of an occluded blood vessel. Less commonly, stroke results from the absence of blood flow to the entire brain due to cardiac arrest. In all instances, stroke ultimately involves death and dysfunction of brain cells, and neurological deficits that reflect the location and size of the compromised brain area. In July 2001, the National Institutes of Neurological Disorders and Stroke convened the Stroke Program Review Group to advise on directions for basic and clinical stroke research for the next decade. This meeting emphasized the relevance of dynamic interactions between endothelial cells, vascular smooth muscle, astroglia and microglia, neurons and associated tissue matrix proteins — the neurovascular unit — and its importance to disease pathophysiology. The neurovascular unit places stroke in the context of an integrative tissue response in which all cellular and matrix elements, not just neurons or blood vessels, are players in the evolution of tissue injury. The concept might also apply to other brain disorders in which there is a significant vascular component, such as VASCULAR DEMENTIA, migraine, trauma, MULTIPLE SCLEROSIS and, possibly, the ageing brain. This review will focus on emerging concepts in stroke involving relevant components of the neurovascular unit, as well as highlighting those that are promising targets for stroke therapy. It will begin by briefly discussing risk factors. It will then highlight major mechanisms of cellular injury, and focus on mechanisms and tissue processes that we see as crucial to potential positive developments in stroke therapy.