Toward safer thrombolytic agents in stroke: Molecular requirements for NMDA receptor-mediated neurotoxicity

Jose P Lopez-Atalaya, Benoit D Roussel, Denis Levrat, Jérôme Parcq, Olivier Nicole, Yannick Hommet, Karim Benchenane, Hervé Castel, Jérôme Leprince, Denis To Van, Ronan Bureau, Sylvain Rault, Hubert Vaudry, Karl-Uwe Petersen, Jana Sopkova-de Oliveira Santos, Carine Ali, Denis Vivien
J Cereb Blood Flow Metab. 2008-03-12; 28(6): 1212-1221
DOI: 10.1038/jcbfm.2008.14

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1. J Cereb Blood Flow Metab. 2008 Jun;28(6):1212-21. doi: 10.1038/jcbfm.2008.14.
Epub 2008 Mar 12.

Toward safer thrombolytic agents in stroke: molecular requirements for NMDA
receptor-mediated neurotoxicity.

Lopez-Atalaya JP(1), Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y,
Benchenane K, Castel H, Leprince J, To Van D, Bureau R, Rault S, Vaudry H,
Petersen KU, Santos JS, Ali C, Vivien D.

Author information:
(1)INSERM, INSERM U919 ‘serine proteases and pathophysiology of the neurovascular
unit’, GIP Cyceron, Caen Cedex, France.

Current thrombolytic therapy for acute ischemic stroke with tissue-type
plasminogen activator (tPA) has clear global benefits. Nevertheless, evidences
argue that in addition to its prohemorrhagic effect, tPA might enhance
excitotoxic necrosis. In the brain parenchyma, tPA, by binding to and then
cleaving the amino-terminal domain (ATD) of the NR1 subunit of
N-methyl-D-aspartate (NMDA) glutamate receptors, increases calcium influx to
toxic levels. We show here that tPA binds the ATD of the NR1 subunit by a
two-sites system (K(D)=24 nmol/L). Although tenecteplase (TNK) and reteplase also
display two-sites binding profiles, the catalytically inactive mutant TNKS478A
displays a one-site binding profile and desmoteplase (DSPA), a kringle 2 (K2)
domain-free plasminogen activator derived from vampire bat, does not interact
with NR1. Moreover, we show that in contrast to tPA, DSPA does not promote
excitotoxicity. These findings, together with three-dimensional (3D) modeling,
show that a critical step for interaction of tPA with NR1 is the binding of its
K2 domain, followed by the binding of its catalytic domain, which in turn cleaves
the NR1 subunit at its ATD, leading to a subsequent potentiation of NMDA-induced
calcium influx and neurotoxicity. This could help design safer new generation
thrombolytic agents for stroke treatment.

DOI: 10.1038/jcbfm.2008.14
PMID: 18334994 [Indexed for MEDLINE]


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