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

• Published in: Stroke (1970) Vol. 38; no. 3; pp. 1036 - 1043
• Main Authors: LOPEZ-ATALAYA, Jose P, ROUSSEL, Benoit D, ALI, Carine, MAUBERT, Eric, PETERSEN, Karl-Uwe, BEREZOWSKI, Vincent, ROMEO, Cecchelli, ORSET, Cyrille, VIVIEN, Denis
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.03.2007; American Heart Association
• Subjects: Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Cattle; Cells, Cultured; Chiroptera; Coculture Techniques; Desmodus rotundus; Fibrinolytic Agents - pharmacokinetics; Fibrinolytic Agents - toxicity; Humans; Life Sciences; Low Density Lipoprotein Receptor-Related Protein-1 - physiology; Male; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Plasminogen Activators - pharmacokinetics; Plasminogen Activators - toxicity; Rats; Rats, Sprague-Dawley; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - toxicity; Vascular diseases and vascular malformations of the nervous system; Vascular disease; Stroke; Nervous system diseases; Toxicity; Desmoteplase; Excitotoxicity; blood-brain barrier ■ desmoteplase ■ excitotoxicity ■ stroke ■ thrombolysis; Central nervous system disease; Cardiovascular disease; Blood brain barrier; Cerebrovascular disease; Cerebral disorder; Blood-brain barrier; Thrombolysis
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.STR.0000258100.04923.84

Desmoteplase, a recombinant form of the plasminogen activator DSPAalpha1 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. 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. 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. 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.