title: tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1.
abstract: Traumatic brain injury (TBI) is associated with loss of cerebrovascular autoregulation, which leads to cerebral hypoperfusion. Mitogen activated protein kinase (MAPK) isoforms ERK, p38, and JNK and endothelin-1 (ET-1) are mediators of impaired cerebral hemodynamics after TBI. Excessive tissue plasminogen activator (tPA) released after TBI may cause loss of cerebrovascular autoregulation either by over-activating N-methyl-D-aspartate receptors (NMDA-Rs) or by predisposing to intracranial hemorrhage. Our recent work shows that a catalytically inactive tPA variant (tPA-S(481)A) that competes with endogenous wild type (wt) tPA for binding to NMDA-R through its receptor docking site but that cannot activate it, prevents activation of ERK by wt tPA and impairment of autoregulation when administered 30 min after fluid percussion injury (FPI). We investigated the ability of variants that lack proteolytic activity but bind/block activation of NMDA-Rs by wt tPA (tPA-S(481)A), do not bind/block activation of NMDA-Rs but are proteolytic (tPA-A(296-299)), or neither bind/block NMDA-Rs nor are proteolytic (tPA-A(296-299)S(481)A) to prevent impairment of autoregulation after TBI and the role of MAPK and ET-1 in such effects. Results show that tPA-S(481)A given 3 h post-TBI, but not tPA-A(296-299) or tPA-A(296-299)S(481)A prevents impaired autoregulation by upregulating p38 and inhibiting ET-1, suggesting that tPA-S(481)A has a realistic therapeutic window and focuses intervention on NMDA-Rs to improve outcome.
authors.affiliation: 1 Department of Anesthesiology and Critical Care, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Leif-Erik
authors.initials: LE
authors.lastname: Bohman
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: Serge
authors.initials: S
authors.lastname: Yarovoi
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
chemical_list: D019332:Endothelin-1; D016194:Receptors, N-Methyl-D-Aspartate; D048051:p38 Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator