Pathophysiology of stroke: lessons from animal models.
The current pathophysiological understanding of stroke is substantially based on experimental studies. Brain injury after cerebral ischemia develops from a complex signaling cascade that evolves in an at least partially unraveled spatiotemporal pattern. Early excitotoxicity can lead to fast necrotic cell death, which produces the core of the infarction. The ischemic penumbra that surrounds the infarct core suffers milder insults. In this area, both mild excitotoxic and inflammatory mechanisms lead to delayed cell death, which shows biochemical characteristics of apoptosis. While brain cells are challenged by these deleterious mechanisms, they activate innate protective programs of the brain, which can be studied by means of experimentally inducing ischemic tolerance (i.e., ischemic preconditioning). Importantly, cerebral ischemia not only affects the brain parenchyma, but also impacts extracranial systems. For example, stroke induces a dramatic immunosuppression via an overactivation of the sympathetic nervous system. As a result, severe bacterial infections such as pneumonia occur. Complex signaling cascades not only decide about cell survival, but also about the neurological deficit and the mortality after stroke. These mechanisms of damage and endogenous protection present distinct molecular targets that are the rational basis for the development of neuroprotective drugs.
Mergenthaler
Philipp
P
Department of Experimental Neurology Charité, Humboldt University, Berlin, Germany. andreas.meisel@charite.de
Dirnagl
Ulrich
U
Meisel
Andreas
A
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D019194:Ischemic Preconditioning; D009410:Nerve Degeneration / Q000209:etiology / Q000503:physiopathology*; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*