Over the last decade, tissue type plasminogen activator (tPA) has been implicated in a variety of brain functions. It is secreted from growth cones or extending neurites, modulates neurite outgrowth and promotes neuronal migration in vitro. tPA has also been involved in glutamatergic-dependent processes such as synaptic plasticity and long term potentiation. For example, tPA deficient mice display alterations in learning paradigms and memory processes. Similarly, tPA has been shown to play an important role in the pathogenesis of seizures, multiple sclerosis, trauma and ischemic brain injury 1. Thrombolysis by tissue type plasminogen activator (tt-PA) is currently the only approved treatment in acute ischemic stroke (NINDS, 1995)2. However, experimental models suggest that rt-PA could have deleterious effects by potentiating ischemic neuronal death. We have previously demonstrated that rt-PA promotes excitotoxic neuronal death by interacting with and cleaving the N-terminus of the NMDA receptor NR1 subunit, at arginine 260, thereby augmenting NMDA receptor-signalling 3–4. DSPA is a related plasminogen activator derived from bat saliva and lacks the Kringle2 domain. More recently, DSPA administered 3 to 9 hours after acute ischemic stroke in man, has been shown to produce high reperfusion rates and an improved clinical outcome with a favorably low bleeding risk 5. In this study, we demonstrate that DSPA, unlike rt-PA, neither interacts with nor cleaves the NR1 subunit. These data are consistent with the observation that, in contrast to rt-PA, DSPA does not potentiate NMDA-induced neuronal death in murine models 6. They provide a molecular basis that possibly explains why DSPA has a more favorable profile compared to rt-PA in the treatment of acute ischemic stroke.
