The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke

Many physicians nihilistically view ischemic stroke as a “cerebrovascular accident” caused by the homogeneous loss of blood supply, oxygen tension, and highenergy metabolites in an area of brain that will inevitably become necrotic. Fortunately, most neurologists experienced with the patient with an acute hemiparesis who recovers normal motor function within 24 hours recognize the complex, variable nature of blood flow loss in stroke and the potential for reversing the events that cause cerebral infarction. This notion of reversible brain injury stimulates clinical scientists to unravel the pathophysiology of focal brain ischemia and to develop new treatments to protect brain against evolving ischemic necrosis. It is in this setting that the ischemic penumbra-that zone of ischemically threatened tissue adjacent to the core zone of an evolving focal ischemic infarction-assumes clinical relevance well beyond the phenomenological curiosity of experimental animal research. In this issue Professor Hossmann 111 does a service by nicely summarizing our current knowledge of the ischemic penumbra and by focusing attention o n its importance to clinical stroke. That such a zone exists and is amenable to acute therapy is evidenced by the impressive success of a variety of experimental therapeutic approaches in achieving a 50% or greater reduction of infarct volume when treatment is initiated soon after the onset of ischemic stroke 123. Examples of successful approaches include glutamate antagonism at N-methyhaspartate (NMDA) and non-NMDA receptors, mild to moderate hypothermia, blockade of certain calcium channels, antagonism of oxygen radicals, and several other pharmacological agents with less well-defined mechanisms of action 133. We wish to challenge, however, the definition of the ischemic penumbra set forth by Professor Hossmann-that is, a “region of constrained blood supply in which energy metabolism is preserved” 113. The very data adduced by Professor Hossmann support the concept that the penumbra is threatened precisely owing to the fact it is besieged by intermittent bioenergetic cornpromire. In this regard, the distinction between spreading depression and the recurrent depolarizations or persistent depolarization that develop in regions of the penumbra and ischemic core, respectively, is crucial. Spreading depression is elicited experimentally in normal cortex by, for example, local potassium chloride application; the negative shift of DC potential, reflecting massive cellular depolarization with an increase in extracellular potassium and a decrease in extracellular calcium ions, is accompanied by increased oxygen and substrate utilization, which are adequately matched to local cerebral blood flow (CBF) responses 141. Spreading depression in normal tissue does not lead to histological injury. By contrast, recurrent depolarizations occurring in periinfarct tissue give rise to similar ionic translocations and hence comparable energy demands, but unlike CBF in the normal brain, CBF in the penumbra is unable to increase. As a result, high-energy metabolites (ATP and phosphocreatine) are intermittently reduced. Takeda and colleagues 151 clearly showed partial ATP and phosphocreatine depletion when ischemic penumbral tissue is assayed during a recurrent depolarization, and total ATP depletion when tissue metabolites are assessed during persistent anoxic depolarization, that is, the condition associated with maximal K’, increases. Though it is difficult to measure intracellular calcium ion in vivo, one would predict that these waves of bioenergetic failure in the penumbral tissue would lead to successive and eventually lethal increases in intracellular free calcium-a widely accepted final common pathway of irreversible neuronal injury [b]. Thus, the penumbral condition is metastable precisely because the ensuing intermittent or sustained metabolic demand (and hence heightened energy expenditure) is uncoupled from (i.e., not accompanied by) a proportionate increase in local CBF. Deoxyglucose autoradiography in animals consistently shows zones of relative or absolute glucose hypermetabolism affecting the periinfarct region during the first 2 hours after onset of ischemia, which reverts to hypometabolism as the penumbra deteriorates and merges with the ischemic core by 3 to 4 hours {7]. Accordingly, a more accurate definition of the ischemic penumbra is as follows: brain tissue in which the CBF has decreased to the point of causing electrophysiological silence (i.e., an isoelectric electroencephalogram) and transient but recurrent losses of membrane ion gradients and energy metabolites. The precise cause for these recurrent depolaritations is unknown, but the release of the excitatory neurotransmitter glutamate, whose rise in the penumbra is directly related to the extent of the CBF decrement 181, may be one