Today there exists only one FDA-approved treatment for ischemic stroke; i.e., 
the serine protease tissue-type plasminogen activator (tPA). In the aftermath of 
the failed stroke clinical trials with the nitrone spin trap/radical scavenger, 
NXY-059, a number of articles raised the question: are we doing the right thing? 
Is the animal research truly translational in identifying new agents for stroke 
treatment? This review summarizes the current state of affairs with plasminogen 
activators in thrombolytic therapy. In addition to therapeutic value, potential 
side effects of tPA also exist that aggravate stroke injury and offset the 
benefits provided by reperfusion of the occluded artery. Thus, combinational 
options (ultrasound alone or with microspheres/nanobubbles, mechanical 
dissociation of clot, activated protein C (APC), plasminogen activator 
inhibitor-1 (PAI-1), neuroserpin and CDP-choline) that could offset tPA toxic 
side effects and improve efficacy are also discussed here. Desmoteplase, a 
plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, 
antagonizes vascular tPA-induced neurotoxicity by competitively binding to 
low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) 
interface, minimizing the tPA uptake into brain parenchyma. tPA can also 
activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised 
of 24 mammalian enzymes that primarily catalyze the turnover and degradation of 
the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and 
neuronal injury in the early times after stroke, but also contribute to vascular 
remodeling, angiogenesis, neurogenesis and axonal regeneration during the later 
repair phase after stroke. tPA, directly or by activation of MMP-9, could have 
beneficial effects on recovery after stroke by promoting neurovascular repair 
through vascular endothelial growth factor (VEGF). However, any treatment 
regimen directed at MMPs must consider their pleiotropic nature and the 
likelihood of either beneficial or detrimental effects that might depend on the 
timing of the treatment in relation to the stage of brain injury.