This Article Full Text Full Text (PDF) All Versions of this Article: 34/2/537    most recent 01.STR.0000049764.49162.76v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Liberatore, G. T. Articles by Medcalf, R. L. Search for Related Content PubMed PubMed Citation Articles by Liberatore, G. T. Articles by Medcalf, R. L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Degenerative Nerve Diseases Related Collections Animal models of human disease Genetically altered mice Fibrinolysis Thrombolysis

(Stroke. 2003;34:537.)
© 2003 American Heart Association, Inc.

Original Contributions

Vampire Bat Salivary Plasminogen Activator (Desmoteplase)

A Unique Fibrinolytic Enzyme That Does Not Promote Neurodegeneration

Gabriel T. Liberatore, PhD; André Samson, BSc; Christopher Bladin, MD; Wolf-Dieter Schleuning, MD, PhD Robert L. Medcalf, PhD

From the Department of Medicine, Monash University, Box Hill Hospital, Victoria, Australia (G.T.L., A.S., C.B., R.L.M.); Eastern Melbourne Neurosciences, Victoria, Australia (G.T.L., C.B.); and PAION GmbH Research Center, Berlin, Germany (W-D.S.).

Reprint requests to Robert L. Medcalf, PhD, Department of Medicine, Monash University, Box Hill Hospital, Box Hill, Victoria 3128, Australia. E-mail robert.medcalf{at}med.monash.edu.au

Background and Purpose— 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.

Key Words: excitotoxins • neuronal death • stroke • tissue plasminogen activator

This article has been cited by other articles:

				L. Pretorius, X.-J. Du, E. A. Woodcock, H. Kiriazis, R. C.Y. Lin, S. Marasco, R. L. Medcalf, Z. Ming, G. A. Head, J. W. Tan, et al. Reduced Phosphoinositide 3-Kinase (p110{alpha}) Activation Increases the Susceptibility to Atrial Fibrillation Am. J. Pathol., September 1, 2009; 175(3): 998 - 1009. [Abstract] [Full Text] [PDF]

				M. W. Parsons, F. Miteff, G. A. Bateman, N. Spratt, A. Loiselle, J. Attia, and C. R. Levi Acute ischemic stroke: Imaging-guided tenecteplase treatment in an extended time window Neurology, March 10, 2009; 72(10): 915 - 921. [Abstract] [Full Text] [PDF]

				C. Orset, R. Macrez, A. R. Young, D. Panthou, E. Angles-Cano, E. Maubert, V. Agin, and D. Vivien Mouse Model of In Situ Thromboembolic Stroke and Reperfusion Stroke, October 1, 2007; 38(10): 2771 - 2778. [Abstract] [Full Text] [PDF]

				K. Danielyan, B.-S. Ding, C. Gottstein, D. B. Cines, and V. R. Muzykantov Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 947 - 952. [Abstract] [Full Text] [PDF]

				K. Ganguly, J.-C. Murciano, R. Westrick, J. Leferovich, D. B. Cines, and V. R. Muzykantov The Glycocalyx Protects Erythrocyte-Bound Tissue-Type Plasminogen Activator from Enzymatic Inhibition J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 158 - 164. [Abstract] [Full Text] [PDF]

				J. P. Lopez-Atalaya, B. D. Roussel, C. Ali, E. Maubert, K.-U. Petersen, V. Berezowski, R. Cecchelli, C. Orset, and D. Vivien 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 Stroke, March 1, 2007; 38(3): 1036 - 1043. [Abstract] [Full Text] [PDF]

				A. J. Furlan, D. Eyding, G. W. Albers, Y. Al-Rawi, K. R. Lees, H. A. Rowley, C. Sachara, M. Soehngen, S. Warach, W. Hacke, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of Safety and Efficacy 3 to 9 Hours After Stroke Onset Stroke, May 1, 2006; 37(5): 1227 - 1231. [Abstract] [Full Text] [PDF]

				K. Ganguly, M. S. Goel, T. Krasik, K. Bdeir, S. L. Diamond, D. B. Cines, V. R. Muzykantov, and J.-C. Murciano Fibrin Affinity of Erythrocyte-Coupled Tissue-Type Plasminogen Activators Endures Hemodynamic Forces and Enhances Fibrinolysis in Vivo J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1130 - 1136. [Abstract] [Full Text] [PDF]

				C. A. Molina and J. L. Saver Extending Reperfusion Therapy for Acute Ischemic Stroke: Emerging Pharmacological, Mechanical, and Imaging Strategies Stroke, October 1, 2005; 36(10): 2311 - 2320. [Abstract] [Full Text] [PDF]

				C. Reddrop, R. X. Moldrich, P. M. Beart, M. Farso, G. T. Liberatore, D. W. Howells, K.-U. Petersen, W.-D. Schleuning, and R. L. Medcalf Vampire Bat Salivary Plasminogen Activator (Desmoteplase) Inhibits Tissue-Type Plasminogen Activator-Induced Potentiation of Excitotoxic Injury Stroke, June 1, 2005; 36(6): 1241 - 1246. [Abstract] [Full Text] [PDF]

				W. Hacke, G. Albers, Y. Al-Rawi, J. Bogousslavsky, A. Davalos, M. Eliasziw, M. Fischer, A. Furlan, M. Kaste, K. R. Lees, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase Stroke, January 1, 2005; 36(1): 66 - 73. [Abstract] [Full Text] [PDF]

				M. Fernandez-Monreal, J. P. Lopez-Atalaya, K. Benchenane, M. Cacquevel, F. Dulin, J.-P. Le Caer, J. Rossier, A.-C. Jarrige, E. T. MacKenzie, N. Colloc'h, et al. Arginine 260 of the Amino-terminal Domain of NR1 Subunit Is Critical for Tissue-type Plasminogen Activator-mediated Enhancement of N-Methyl-D-aspartate Receptor Signaling J. Biol. Chem., December 3, 2004; 279(49): 50850 - 50856. [Abstract] [Full Text] [PDF]

				X. Wang, K. Tsuji, S.-R. Lee, M. Ning, K. L. Furie, A. M. Buchan, and E. H. Lo Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke Stroke, November 1, 2004; 35(11_suppl_1): 2726 - 2730. [Abstract] [Full Text] [PDF]

				E. H. Lo, J. P. Broderick, and M. A. Moskowitz tPA and Proteolysis in the Neurovascular Unit Stroke, February 1, 2004; 35(2): 354 - 356. [Full Text] [PDF]

				T. Hoekstra, J. M. Geleijnse, C. Kluft, E. J. Giltay, F. J. Kok, and E. G. Schouten 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly Stroke, December 1, 2003; 34(12): 2822 - 2828. [Abstract] [Full Text] [PDF]