title: Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13.
abstract: Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Mengchen
authors.initials: M
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Haochen
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Ximin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
mesh_terms: D000071120:ADAMTS13 Protein / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D008297:Male; D051379:Mice; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D005337:Fibrin; D010959:Tissue Plasminogen Activator; D000071120:ADAMTS13 Protein