Brain tissue depolarizations after ischemic stroke are believed to play a vital role in recruiting adjacent penumbral regions of reversible injury into the core area of infarction. Cortical spreading depression (CSD) is a self-propagating wave of electrochemical activity that advances through neural tissues at a rate of 2-5 mm/min, causing prolonged (1-5 min) cellular depolarization, depressed neuro-electrical activity, potassium and glutamate release into adjacent tissue and reversible loss of membrane ionic gradients. CSD is associated with a change in the levels of numerous factors including immediate early genes, growth factors, and inflammatory mediators such as inter-leukin-1b and TNF-a . CSD is a reversible phe-nomenon,and,while implicated in conditions such as migraine, reportedly does not cause permanent tissue injury in humans. In severely ischemic regions, energy failure is so profound that ionic disturbances and simultaneous depolarizations become permanent, a process termed anoxic depolarization . In penumbral regions after stroke, where blood supply is compromised, spreading depression exacerbates tissue damage, perhaps due to the increased energy requirements for reestablishing ionic equilibrium in the metabolically compromised ischemic tissues. In this context, spreading depression waves are referred to as peri-infarct depolarizations (PIDs) , reflecting their pathogenic role and similarity to anoxic depolarization.
PIDs have been demonstrated in mice, rat, and cat stroke models [72, 73]; however, their relevance to human stroke pathophysiology remains unclear. In the initial 2-6 h after experimental stroke, PIDs result in a step-wise increase in the region of core-infarcted tissue into adjacent penumbral regions [74,75], and the incidence and total duration of spreading depression is shown to correlate with infarct size . Recent evidence suggests that PIDs contribute to the expansion of the infarct core throughout the period of infarct maturation . Inhibition of spreading depression using pharmaceutical agents such as NMDA or glycine antagonists [77,78], or physiological approaches such as hypothermia , could be an important strategy to suppress the expansion of an ischemic lesion.
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