Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration.
OBJECTIVE
Tissue-type plasminogen activator (tPA) promotes excitotoxic and ischemic injury within the brain. These findings have implications for the use of tPA in the treatment of acute ischemic stroke. The plasminogen activator from vampire bat (Desmodus rotundus) saliva (D rotundus salivary plasminogen activator [DSPA]; desmoteplase) is an effective plasminogen activator but, in contrast to tPA, is nearly inactive in the absence of a fibrin cofactor. The purpose of this study was to compare the ability of DSPA and tPA to promote kainate- and N-methyl-D-aspartate (NMDA)-induced neurodegeneration in tPA-/- mice and wild-type mice, respectively.


METHODS
tPA-/- mice were infused intracerebrally with either tPA or DSPA. The degree of neuronal survival after hippocampal injection of kainate was assessed histochemically. Wild-type mice were used to assess the extent of neuronal damage after intrastriatal injection of NMDA in the presence of tPA or DSPA. Immunohistochemistry and fibrin zymography were used to evaluate DSPA and tPA antigen or activity.


RESULTS
Infusion of tPA into tPA-/- mice restored sensitivity to kainate-mediated neurotoxicity and activation of microglia. DSPA was incapable of conferring sensitivity to kainate treatment, even when infused at 10-fold higher molar concentration than tPA. The presence of tPA also increased the lesion volume induced by NMDA injection into the striatum of wild-type mice, whereas DSPA had no effect.


CONCLUSIONS
DSPA does not promote kainate- or NMDA-mediated neurotoxicity in vivo. These results provide significant impetus to evaluate DSPA in patients with ischemic stroke.
Liberatore
Gabriel T
GT
Department of Medicine, Monash University, Box Hill Hospital, Victoria, Australia.
Samson
André
A
Bladin
Christopher
C
Schleuning
Wolf-Dieter
WD
Medcalf
Robert L
RL
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016202:N-Methylaspartate; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010960:Plasminogen Activators / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*
D005343:Fibrinolytic Agents; C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D016202:N-Methylaspartate; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D007608:Kainic Acid