title: tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury.
abstract: Traumatic brain injury (TBI) is associated with loss of autoregulation due to impaired responsiveness to cerebrovascular dilator stimuli, which leads to cerebral hypoperfusion and neuronal impairment or death. Upregulation of tissue plasminogen activator (tPA) post-TBI exacerbates loss of cerebral autoregulation and NMDA-receptor-mediated impairment of cerebral hemodynamics, and enhances excitotoxic neuronal death. However, the relationship between NMDA-receptor activation, loss of autoregulation, and neurological dysfunction is unclear. Here, we evaluated the potential therapeutic efficacy of a catalytically inactive tPA variant, tPA S481A, that acts by competing with wild-type tPA for binding, cleavage, and activation of NMDA receptors. Lateral fluid percussion brain injury was produced in anesthetized piglets. Pial artery reactivity was measured via a closed cranial window, and cerebrospinal fluid (CSF) extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) was quantified by enzyme-linked immunosorbent assay (ELISA). tPA-S481A prevented impairment of cerebral autoregulation and reduced histopathologic changes after TBI by inhibiting upregulation of the ERK isoform of MAPK. Treatment with this tPA variant provides a novel approach for limiting neuronal toxicity caused by untoward NMDA-receptor activation mediated by increased tPA and glutamate following TBI.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. armsteaw@uphs.upenn.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Serge
authors.initials: S
authors.lastname: Yarovoi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Smith
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000473:pathology; D002536:Cerebral Arteries / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D016133:Polymerase Chain Reaction; D011453:Prostaglandins / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000134:cerebrospinal fluid / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D011453:Prostaglandins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator