The pleiotropic effects of tissue plasminogen activator in the brain: implications for stroke recovery

Tissue plasminogen activator (tPA) use in the treatment of ischemic stroke: tPA is a serine protease that catalyzes the breakdown of blood clots. Because of its thrombolytic properties, tPA is used to treat specific types of stroke, including ischemia, but is contraindicated for treatment of hemorrhagic stroke or head trauma. Although a life saving and powerful ‘clot buster’, tPA has a short therapeutic window. When administered outside of this prescribed timeframe, research suggests that tPA can produce neurotoxic effects in the brain, due in part to activation of several signalling processes associated with cell apoptosis, degradation of the extracellular matrix, and increase in the permeability of the neurovascular unit (Yepes et al., 2009). Concerted research has been dedicated toward understanding the mechanisms mediating the impact of tPA on the brain, using both in vivo and in vitro animal models. Despite the success of repeated clinical trials and a growing research base pointing to the involvement of several underlying cellular mechanisms mediating the effect of tPA, including an emerging role for mammalian target of rapamycin (mTOR)-dependent signaling, the precise impact of tPA on neurons at the cellular level remains unclear. Furthermore, the widespread clinical use of tPA, for the treatment of acute ischemic stroke, supports the critical nature of establishing a better understanding of the underlying molecular processes mediating the effects of tPA in the brain. This perspective briefly examines current research focusing on the underlying mechanisms mediating the proposed effects of tPA on the brain.