The complexity of tissue-type plasminogen activator: can serine protease inhibitors help in stroke management?

Stroke, the third leading cause of death in industrialised countries, represents a major burden on healthcare authorities. The elucidation of molecular events sustaining infarct evolution in experimental models has allowed the development of putative therapeutic agents. However, despite marked benefits in animals, most of them have failed in clinical trials. At present, the only approved therapy for stroke is early reperfusion by intravenous injection of the thrombolytic agent, tissue-type plasminogen activator (tPA). tPA-dependent thrombolysis sometimes promotes haemorrhage, but improves neurological outcome in a great proportion of patients, provided it is performed within the recommended therapeutic window. In addition to the benefit of tPA injection in the vascular compartment, this endogenously produced serine protease could also promote excitotoxic processes within the cerebral parenchyma. This article reviews the various aspects of tPA during stroke, and discusses potential improvements to current clinical management, with a particular emphasis on targeting the deleterious actions of tPA through endogenous serine protease inhibitors (serpins).