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.
OBJECTIVE
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.


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.
López-Atalaya
José P
JP
INSERM-Avenir, Caen Cedex, France. jose.lopez@umh.es
Roussel
Benoit D
BD
Ali
Carine
C
Maubert
Eric
E
Petersen
Karl-Uwe
KU
Berezowski
Vincent
V
Cecchelli
Roméo
R
Orset
Cyrille
C
Vivien
Denis
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D002685:Chiroptera; D018920:Coculture Techniques; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D008297:Male; D010960:Plasminogen Activators / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000493:pharmacokinetics* / Q000633:toxicity
D005343:Fibrinolytic Agents; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011994:Recombinant Proteins; C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D010960:Plasminogen Activators