A radical approach to stroke therapy

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Abstract
Stroke is a major cause of death and disability throughout the developed world. Cerebrovascular disease ranks third after cancer and heart disease as a cause of death in the European Union and the U.S. The economic and social burdens of stroke are not consequences of mortality; they are imposed by the large majority of stroke patients who survive but are physically and mentally disabled by stroke-induced brain damage. In the U.S., less than 2% of stroke patients benefit from access to early thrombolysis, which removes the primary cause of blood flow reduction. However, no treatment is presently available that protects brain tissue from the multiple neurochemical cascades initiated by both ischemia and reperfusion, and it is these cascades that ultimately cause irreversible brain damage. Oxidative damage does not occur in isolation but participates in the complex interplay between excitotoxicity, apoptosis, and inflammation in ischemia and reperfusion. Over the last decade, remarkable insight has been gained into the neurochemical mechanisms that contribute to ischemic brain damage, and there is compelling evidence that oxidative damage plays an important role. Two papers in this issue of PNAS test the therapeutic potential of reducing oxidative damage in animal models of ischemic brain damage (1, 2). However, the two studies use quite different conceptual and pharmacological approaches. The study of Huang et al. (1) is primarily concerned with the anti-ischemic efficacy of the long-recognized antioxidant ascorbic acid and uses a prodrug treatment strategy with dehydroascorbic acid to deliver ascorbic acid to the central nervous system. The study of Namura et al. (2) focuses on establishing the participation of specific mitogen-activated protein kinases and, after characterizing their involvement in ischemia, examines whether pharmacological inhibition of the kinases alters the outcome after ischemia. By using pharmacological agents that act at quite different points in the oxidative …