This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by López-Atalaya, J. P. Articles by Vivien, D. Search for Related Content PubMed PubMed Citation Articles by López-Atalaya, J. P. Articles by Vivien, D. Related Collections Acute Cerebral Infarction Thrombolysis

(Stroke. 2007;38:1036.)
© 2007 American Heart Association, Inc.

Original Contributions

Recombinant Desmodus rotundus Salivary Plasminogen Activator Crosses the Blood–Brain Barrier Through a Low-Density Lipoprotein Receptor-Related Protein-Dependent Mechanism Without Exerting Neurotoxic Effects

José P. López-Atalaya, PhD; Benoit D. Roussel, MSc; Carine Ali, PhD; Eric Maubert, PhD; Karl-Uwe Petersen, MD; Vincent Berezowski, PhD; Roméo Cecchelli, PhD; Cyrille Orset, PhD Denis Vivien, PhD

From INSERM (J.P.L.-A., B.D.R., C.A., E.M., C.O., D.V.), INSERM-Avenir, Caen Cedex, France, Université de Caen Basse-Normandie, Caen Cedex, France, and GIP Cyceron, Caen, France; PAION Deutschland GmbH (K.-U.P.), Aachen, Germany; Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (V.B., R.C.), Université d’Artois, Faculté des sciences Jean Perrin, France.

Correspondence to Denis Vivien or José P. López-Atalaya, INSERM-Avenir, GIP Cyceron, Bd H.Becquerel, BP 5229, 14074 Caen, France. E-mail vivien{at}cyceron.fr or jose.lopez@umh.es

Background and Purpose— Desmoteplase, a recombinant form of the plasminogen activator DSPA1 from Desmodus rotundus, may offer improved clinical benefits for acute ischemic stroke treatment over the current therapy, recombinant tissue plasminogen activator (rtPA). Accumulating evidence suggests that clinical use of rtPA could be limited by unfavorable properties, including its ability to cross the blood–brain barrier (BBB), thus potentially adding to the pro-excitotoxic effect of endogenous tPA in cerebral parenchyma. Here, to investigate whether desmoteplase may display a safer profile than the structurally-related tPA, both agents were compared for their ability to cross the BBB and promote neurotoxicity.

Methods— First, the passage of vascular DSPA and rtPA was investigated in vitro in a model of BBB, subjected or not to oxygen and glucose deprivation. Second, we studied DSPA- and rtPA-mediated effects in an in vivo paradigm of excitotoxic necrosis.

Results— The rtPA and desmoteplase cross the intact BBB by LRP-mediated transcytosis. Under conditions of oxygen and glucose deprivation, translocation rates of both compounds increased; however, unlike rtPA, desmoteplase transport remained LRP-dependent. Additionally, neither intracerebral nor intravenous desmoteplase administration enhanced NMDA-induced excitotoxic striatal damage in vivo. Interestingly, intravenous but not intrastriatal coadministration of desmoteplase and rtPA reduced the pro-excitotoxic effect of rtPA.

Conclusions— We show that desmoteplase crosses the BBB but does not promote neuronal death. Moreover, intravenous administration of desmoteplase antagonizes the neurotoxicity induced by vascular rtPA. This action may be caused by competition of desmoteplase with rtPA for LRP binding at the BBB, thus effectively blocking rtPA access to the brain parenchyma.

Key Words: blood–brain barrier • desmoteplase • excitotoxicity • stroke thrombolysis