tPa, Stroke and Memory
During my thesis, I studied the role of a protease involved in thrombolysis (destruction of blood clot) the tissue-type plasminogen activator (tPA), which is so far the only available treatment for stroke in human (Benchenane et al. Trends Neurosci 2004). But tPA is also capable of cleaving the NR1 sub-unit of the NMDA receptor leading to an increase in calcium influx into the neurons that enhance ischemic neuronal death (Nicole et al., 2001, Fernandez-Monreal et al., J Biol Chem 2004).
The aim is therfore to enhance tPA efficiency in clinical practice by preventing the deleterious effect of tPA in the brain parenchyma without affecting it beneficial effect in the vascular compartment. Two strategies can be used for this purpose: 1) blockade of the crossing of the blood brain barrier (BBB) and 2) prevent its effect directly in the brain parenchyma.
I have shown that tPA crosses the intact blood-brain barrier and that this was mediated by transcytosis mediated by a receptor: the LDL receptor?related protein (Benchenane et al. Circulation 2005, Benchenane et al., Stroke 2005). However, therapeutic strategy that aim at blocking this receptor is not usable since this receptor is also involve in clearance of the tPA from the blood. This might enhanced the level of circulating tPA which might increase the risk of hemorrhagic transformation.
We then study the action mechanism of tPA in the brain parenchyma. I have shown that vaccination with the recombinant ATD-NR1 (that leads to the generation of antibody which prevent the cleavage of the NMDA receptor by the tPA) was neuroprotective in a model of cerebral ischemia and also prevents the potentiating effect of tPA on NMDA-induced striatal lesion in mice (Benchenane et al., J Cell Sci 2007). This strategy is currently in pre-clinical test, and a patent has been done in collaboration with a pharmaceutical company in order to perform a clinical trial with the co-administration of tPA and the antibody.
Interestingly, tPA is also involved in learning and memory and is induced after protocols of long-term potentiation. We have shown in vivo that the cleavage of the NMDA receptor by the tPA was important for memory since this protocol of vaccination leads to deficits in spatial and social memory (Benchenane et al., J Cell Sci 2007). This shows in vivo that the cleavage of the NMDA receptor is a new way to modulate its function and a new way to mediate the formation of new memory traces.