About 600,000 Americans suffer ischemic stroke each year, 8% of which die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke us therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only one agent is approved (Alteplase, rt-PA), and for only a brief window of time (onset of symptoms less than three hours). Since many patients present far beyond this three hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity the pharmaceutical industry is currently focusing on the development of molecules able to protect neural tissue from ischemic damage. The ischemic excitotoxic cascade that is activated following stroke is well characterized and has resulted in the proposal of a number of pharmacological targets. Molecules developed against these targets have however been largely unsuccessful in the clinic. A further area of study has, paradoxically, focused on the ability of key components of the thrombolytic pathway to mediate neural degeneration in response to excitotoxic molecules/cerebral ischemia. In a ground-breaking study, Tsirka et al (1995) demonstrated that mice deficient in t-PA are resistant to neuronal degeneration produced by exitotoxic molecules. More recently it has been shown by researchers at the University of Leuvens (see our recent dossier "Microplasmin, a novel neuroprotective thrombolytic agent for the treatment of ischemic stroke") that inactivation of the t-PA gene reduces the size of infarcts in murine models of stroke. University of Zurich researchers have also been investigating t-PA as a target for the treatment of stroke. This group showed that following focal occlusion, microglial cells accumulating in the marginal zone of infarcts are the major source of the plasminogen activators, t-PA and uPA. Transgenic mice overexpressing the endogenous t-PA antagonist, neuroserpin, were characterized by reduced levels of total t-PA, 30% smaller infarcts, and attenuation of microglial activation in the reactive zone. Thus therapies able to increase neuroserpin-like activity may offer a new approach to neuroprotection following stroke, although the possible risks relating to a worsening of the thrombotic state should be considered. A similar strategy has already been developed by SuperGen who, as described in the "Focus on CNS disease" section of this edition of TherapeuticAdvances who were investigating stroke as an additional indication for the recombinant serpin, LEX-032.

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