tPA in traumatic brain injury

Summary

Principal Investigator: Abd Al Roof Higazi
Abstract: Traumatic brain injury (TBI) remains a major cause of death and long-term morbidity. Cerebral edema is a common and ominous sequel of severe TBI which results from loss of blood-brain-barrier (BBB) integrity and hemorrhage in the affected zone. This application is predicated on recent data showing that tPA-/- mice are relatively protected from developing cerebral edema and cortical necrosis after TBI and our finding that tPA increases BBB permeability both directly and indirectly by inducing vasorelaxation through extra-fibrinolytic mechanisms that involve signal transduction through the low density lipoprotein related receptor (LRP) and the integrin avb3. Here, we propose to study how the extra-fibrinolytic activities of tPA modulate BBB permeability, vasorelexation, cerebral edema and neurological outcome in experimental TBI. Our approach includes basic research into the mechanism of tPA-mediated signal transduction using antagonists and tPA variants that dissociate its vasoactive and catalytic properties through three inter-related specific aims. In Specific Aim 1 we will study the molecular determinants required to form complexes between avb3 and LRP and mechanism by which tPA disrupts these complexes and induces BBB permeability and vasorelaxation. In Specific Aim 2 the effect of intravascular thrombosis on the development of post-traumatic brain injury will be elucidated using approaches to isolate the fibrinolytic and signal transduction activities of tPA. In Specific Aim 3 the effect of antagonists to LRP and avb3 and tPA variants selectively lacking fibrinolytic or extra-fibrinolytic function in the sequelae of TBI will be examined in wild type and tPA-/- mice. Also, a new approach to deliver tPA to traumatized vessels will be evaluated using platelet-tPA expressing transgenic mice. Together, these studies will provide new understanding of the role of tPA in mediating CNS injury and novel cellular targets and new formulations of tPA that may improve clinical outcome.
Funding Period: 2006-04-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1
    William M Armstead
    1 Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania
    J Neurotrauma 30:1898-907. 2013
  2. pmc Combination therapy with glucagon and a novel plasminogen activator inhibitor-1-derived peptide enhances protection against impaired cerebrovasodilation during hypotension after traumatic brain injury through inhibition of ERK and JNK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Neurol Res 34:530-7. 2012
  3. pmc Red blood cell-coupled tissue plasminogen activator prevents impairment of cerebral vasodilatory responses through inhibition of c-Jun-N-terminal kinase and potentiation of p38 mitogen-activated protein kinase after cerebral photothrombosis in the newborn
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, USA
    Pediatr Crit Care Med 12:e369-75. 2011
  4. pmc tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA l9l04, USA
    Brain Res 1376:88-93. 2011
  5. pmc Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurotrauma 28:451-7. 2011
  6. pmc Flow-dependent channel formation in clots by an erythrocyte-bound fibrinolytic agent
    Kathryn C Gersh
    Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Blood 117:4964-7. 2011
  7. pmc Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase
    Anastasia M Makarova
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 286:23044-53. 2011
  8. pmc Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate
    Rami Abu Fanne
    Department of Clinical Biochemistry, Hadassah Hebrew University Medical Center, Jerusalem, Israel
    Am J Physiol Regul Integr Comp Physiol 301:R668-73. 2011
  9. pmc tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Neurol Res 33:726-33. 2011
  10. pmc tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurotrauma 29:1794-802. 2012

Scientific Experts

  • William Armstead
  • Abd Al Roof Higazi
  • Sherman C Stein
  • Rami Abu Fanne
  • Douglas B Cines
  • Taher Nassar
  • Sergei Zaitsev
  • Samuel N Heyman
  • Anastasia M Makarova
  • Kathryn C Gersh
  • Nuha Hijazi
  • Victoria Stepanova
  • J Willis Kiessling
  • Otailah Waked
  • Maria E Carinato
  • Gadi Goelman
  • John W Weisel
  • Khalil Bdeir
  • Jing Xue
  • Achinoam Mazuz
  • Vladimir Muzykantov
  • Tatiana V Lebedeva
  • Michael Karakoveski
  • Mahmud Jammal
  • Polianski Vadim
  • Sergei Yarovoi
  • M Anna Kowalska
  • Vladimir R Muzykantov
  • Oscar A Marcos-Contreras
  • Samira Tliba
  • Dirk Spitzer
  • Anwar Rayan
  • Bi Sen Ding
  • Alice Kuo
  • Mortimer Poncz
  • Itschak Lamensdorf
  • Juan Carlos Murciano
  • John P Atkinson

Detail Information

Publications22

  1. pmc tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1
    William M Armstead
    1 Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania
    J Neurotrauma 30:1898-907. 2013
    ....
  2. pmc Combination therapy with glucagon and a novel plasminogen activator inhibitor-1-derived peptide enhances protection against impaired cerebrovasodilation during hypotension after traumatic brain injury through inhibition of ERK and JNK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Neurol Res 34:530-7. 2012
    ..This study was designed to investigate relationships between tPA, prostaglandins, and MAPK as a mechanism to improve the efficacy of glucagon-mediated preservation of cerebrovasodilation during hypotension after TBI...
  3. pmc Red blood cell-coupled tissue plasminogen activator prevents impairment of cerebral vasodilatory responses through inhibition of c-Jun-N-terminal kinase and potentiation of p38 mitogen-activated protein kinase after cerebral photothrombosis in the newborn
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, USA
    Pediatr Crit Care Med 12:e369-75. 2011
    ....
  4. pmc tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA l9l04, USA
    Brain Res 1376:88-93. 2011
    ..These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can dysregulate cerebrohemodynamics by impairing cation-mediated control of cerebrovascular tone...
  5. pmc Glucagon protects against impaired NMDA-mediated cerebrovasodilation and cerebral autoregulation during hypotension after brain injury by activating cAMP protein kinase A and inhibiting upregulation of tPA
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurotrauma 28:451-7. 2011
    ....
  6. pmc Flow-dependent channel formation in clots by an erythrocyte-bound fibrinolytic agent
    Kathryn C Gersh
    Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Blood 117:4964-7. 2011
    ..Formation of such channels by RBC-PAs may help rescue ischemic tissue before bulk dissolution of potentially occlusive clots...
  7. pmc Urokinase-type plasminogen activator (uPA) induces pulmonary microvascular endothelial permeability through low density lipoprotein receptor-related protein (LRP)-dependent activation of endothelial nitric-oxide synthase
    Anastasia M Makarova
    Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 286:23044-53. 2011
    ....
  8. pmc Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate
    Rami Abu Fanne
    Department of Clinical Biochemistry, Hadassah Hebrew University Medical Center, Jerusalem, Israel
    Am J Physiol Regul Integr Comp Physiol 301:R668-73. 2011
    ..These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels...
  9. pmc tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Neurol Res 33:726-33. 2011
    ..We hypothesize that tPA impairs NMDA-induced cerebrovasodilation after FPI in a MAPK isoform-dependent mechanism...
  10. pmc tPA-S481A prevents neurotoxicity of endogenous tPA in traumatic brain injury
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurotrauma 29:1794-802. 2012
    ..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...
  11. pmc Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after photothrombosis through inhibition of JNK MAPK
    William M Armstead
    Dept of Anesthesiology and Critical Care, 3620 Hamilton Walk, JM3, Univ of Pennsylvania, Philadelphia, PA 19104, USA
    Am J Physiol Regul Integr Comp Physiol 299:R480-5. 2010
    ..JNK MAPK inhibitors, including PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy and enable its use in central nervous system ischemic disorders...
  12. ncbi Neuroprotection by glucagon: role of gluconeogenesis
    Rami Abu Fanne
    Department of Clinical Biochemistry, MRI MRS lab of the Human Biology Research Center, Hadassah Hebrew University Medical Center, Jerusalem, Israel
    J Neurosurg 114:85-91. 2011
    ..In the present study, the authors asked if reducing glutamate via approaches that do not lower glucose levels would improve neurological outcome following TBI...
  13. pmc PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
    Am J Physiol Heart Circ Physiol 299:H76-80. 2010
    ....
  14. pmc Sustained thromboprophylaxis mediated by an RBC-targeted pro-urokinase zymogen activated at the site of clot formation
    Sergei Zaitsev
    Program in Targeted Therapeutics, Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104 6068, USA
    Blood 115:5241-8. 2010
    ..Thus, prophylactic delivery of RBC-targeted PA pro-drugs activated selectively at the site of clot formation represents a new approach to prevent thrombosis in clinical settings where the risk of clotting is high...
  15. pmc Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurochem 113:303-12. 2010
    ..Additionally, the role of age will be considered since thrombolytic therapy is being increasingly used in the pediatric population, but there are few basic science studies of CNS injury in pediatric animals...
  16. ncbi Blood-brain barrier permeability and tPA-mediated neurotoxicity
    Rami Abu Fanne
    Department of Clinical Biochemistry, Hebrew University Hadassah Medical Center, Jerusalem, Israel
    Neuropharmacology 58:972-80. 2010
    ....
  17. pmc Erythrocyte-bound tissue plasminogen activator is neuroprotective in experimental traumatic brain injury
    Sherman C Stein
    Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19106, USA
    J Neurotrauma 26:1585-92. 2009
    ..01) and hippocampal cell loss ( p<0.01) in the RBC=tPA group than in all other groups. These results reveal that RBC/tPA is more neuroprotective in experimental TBI than is unbound tPA...
  18. pmc uPA modulates the age-dependent effect of brain injury on cerebral hemodynamics through LRP and ERK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Cereb Blood Flow Metab 29:524-33. 2009
    ..These data indicate that uPA is upregulated after FPI and produces an age-dependent early hyperemia followed by histopathology through an LRP- and ERK MAPK-dependent pathway...
  19. pmc Urokinase plasminogen activator impairs SNP and PGE2 cerebrovasodilation after brain injury through activation of LRP and ERK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurotrauma 25:1375-81. 2008
    ..These data indicate that uPA contributes to the impairment of SNP and PGE(2)-mediated cerebrovasodilation seen after brain injury through activation of LRP and ERK MAPK...
  20. pmc Inhibition of integrin alphavbeta3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia
    J Willis Kiessling
    Dept of Anesthesiology and Critical Care, 3620 Hamilton Walk, JM3, Univ of Pennsylvania, Philadelphia, PA l9l04, USA
    Am J Physiol Heart Circ Physiol 296:H862-7. 2009
    ..These data suggest that the inhibition of uPA and integrin signaling may preserve cerebrohemodynamic control after H/I...
  21. pmc Red blood cells-coupled tPA prevents impairment of cerebral vasodilatory responses and tissue injury in pediatric cerebral hypoxia/ischemia through inhibition of ERK MAPK activation
    William M Armstead
    Department of Anesthesiology and Critical Care, 3620 Hamilton Walk, JM3, University of Pennsylvania, Philadelphia, PA l9l04, USA
    J Cereb Blood Flow Metab 29:1463-74. 2009
    ..These data suggest that coupling of tPA to RBCs offers a novel approach toward increasing the benefit/risk ratio of thrombolytic therapy for CNS disorders associated with H/I...
  22. pmc uPA impairs cerebrovasodilation after hypoxia/ischemia through LRP and ERK MAPK
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Brain Res 1231:121-31. 2008
    ..These data suggest that modulation of uPA upregulation and/or uPA-mediated signal transduction may preserve cerebrohemodynamic control after hypoxia/ischemia...