title: Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke.
abstract: High blood levels of α2-antiplasmin have been associated with failed tissue plasminogen activator (TPA) therapy for ischemic stroke. Yet, other data suggests that α2-antiplasmin may be protective in stroke, because it defends against bleeding and excitotoxicity. To address this paradox, we examined the effects of high α2-antiplasmin levels and α2-antiplasmin inactivation in mice treated with TPA 0.5-2.5h after middle cerebral artery (MCA) thromboembolism. Brain infarction, swelling, hemorrhage, blood brain barrier breakdown and neuronal apoptosis were measured by a blinded observer. Thrombus dissolution was determined by gamma counting. During TPA treatment, high α2-antiplasmin blood levels increased brain infarction (2.2-fold) and swelling (3.7-fold), but decreased MCA thrombus dissolution. Conversely, α2-antiplasmin inactivation during TPA treatment reduced brain infarction, hemorrhage and swelling, but increased MCA thrombus dissolution. Inactivation of α2-antiplasmin during TPA treatment reduced neuronal apoptosis and blood brain barrier breakdown. Inactivation of α2-antiplasmin also reduced short-term mortality. Taken together these data show that α2-antiplasmin opposes the effects of TPA therapy and contributes to enhanced brain injury after experimental thromboembolic stroke. Conversely, α2-antiplasmin inactivation during TPA treatment improves thrombus dissolution and reduces brain infarction, swelling and hemorrhage. Consistent with clinical observations, these data suggest that α2-antiplasmin exerts deleterious effects that reduce the efficacy and safety of TPA therapy for ischemic stroke.
authors.affiliation: Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
authors.forename: Aiilyan K
authors.initials: AK
authors.lastname: Houng
authors.affiliation: Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA. Electronic address: glreed@uthsc.edu.
authors.forename: Guy L
authors.initials: GL
authors.lastname: Reed
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D010959:Tissue Plasminogen Activator
keywords: Apoptosis; Edema; Fibrinolysis; Hemorrhage; Mortality; Stroke; Thrombosis