Effects of tissue-type plasminogen activator in acute clinical stroke

A rational approach to cerebral ischemia involves reperfusion of occluded arteries. Recent clinical trials have shown that thrombolytic therapy with tissue-type plasminogen activator (tPA) may be effective for acute ischemic stroke. However, there is also an elevated risk of cerebral hemorrhage and further brain injury. In all three of the major clinical trials (National Institute of Neurological Disorders and Stroke, European Cooperative Acute Stroke Study I and II), the odds ratio for intracerebral hemorrhage after tPA therapy was increased by about three-fold compared with placebo. The precise mechanisms that underlie these negative effects of tPA remain unclear, but are clearly related to severity of the ischemic insult as well as to the timing of tPA-induced reperfusion. In this chapter, the literature on the neurotoxic effects of tPA will be briefly discussed, and data from our own laboratory will be provided with which we examine some of these mechanisms.

Effects of tPA in experimental cerebral ischemia

Although tPA-induced reperfusion of ischemic brain tissue is expected to salvage tissue, recent reports from the experimental literature have suggested that tPA may have neurotoxic effects as well. Wang and colleagues have shown that infusion of tPA increased infarct size in a mouse model of focal cerebral ischemia. Potentially negative effects of tPA may be based on its ability to activate plasminogen and induce damaging extracellular proteolytic pathways. Specifically, non-fibrin substrates for plasmin, such as laminin, may be degraded.