Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury.
OBJECTIVE
In contrast to tissue-type plasminogen activator (tPA), vampire bat (Desmodus rotundus) salivary plasminogen activator (desmoteplase [DSPA]) does not promote excitotoxic injury when injected directly into the brain. We have compared the excitotoxic effects of intravenously delivered tPA and DSPA and determined whether DSPA can antagonize the neurotoxic and calcium enhancing effects of tPA.


METHODS
The brain striatal region of wild-type c57 Black 6 mice was stereotaxically injected with N-methyl-d-Aspartate (NMDA); 24 hour later, mice received an intravenous injection of tPA or DSPA (10 mg/kg) and lesion size was assessed after 24 hours. Cell death and calcium mobilization studies were performed using cultures of primary murine cortical neurons.


RESULTS
NMDA-mediated injury was increased after intravenous administration of tPA, whereas no additional toxicity was seen after administration of DSPA. Unlike DSPA, tPA enhanced NMDA-induced cell death and the NMDA-mediated increase in intracellular calcium levels in vitro. Moreover, the enhancing effects of tPA were blocked by DSPA.


CONCLUSIONS
Intravenous administration of tPA promotes excitotoxic injury, raising the possibility that leakage of tPA from the vasculature into the parenchyma contributes to brain damage. The lack of such toxicity by DSPA further encourages its use as a thrombolytic agent in the treatment of ischemic stroke.
Reddrop
Courtney
C
Australian Centre for Blood Diseases, Monash University, 6th Floor Burnet Institute, AMREP, 89 Commercial Road, Prahran, Victoria 3181, Australia.
Moldrich
Randal X
RX
Beart
Philip M
PM
Farso
Mark
M
Liberatore
Gabriel T
GT
Howells
David W
DW
Petersen
Karl-Uwe
KU
Schleuning
Wolf-Dieter
WD
Medcalf
Robert L
RL
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007511:Ischemia / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000473:pathology; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000494:pharmacology*; D015912:Thrombolytic Therapy / Q000379:methods; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
D005343:Fibrinolytic Agents; C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D016202:N-Methylaspartate; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D002118:Calcium