Plasminogen activators and cerebral ischemic injury

Summary

Principal Investigator: William Armstead
Abstract: DESCRIPTION (provided by applicant): Babies are frequently exposed to hypoxia and ischemia during the perinatal period due to stroke or problems with delivery or respiratory management post delivery. Neonatal stroke incidence can be as high as 1 in 4000 births. One contributor to neurologic damage is cerebrovascular dysfunction. The only FDA approved treatment for acute stroke is the administration of tPA. Nonetheless, in basic science studies, tPA has been observed to exhibit a dual beneficial/deleterious effect. In addition to its salutary role in reperfusion, tPA may contribute to neuronal cell death. A potential explanation for the tPA therapeutic treatment paradox could relate to the vascular activity (dilation) of tPA. The term neurovascular unit (NVU) focuses attention on the interactions between cerebral blood vessels and neurons. Mitogen activated protein kinase (MAPK) expression is enhanced after cerebral ischemia and may be one of the most distal systems affecting both the vasculature and genomics. The hypothesis is that plasminogen activator production following cerebral hypoxia/ischemia contributes to impaired cerebral hemodynamics and neuronal cell loss post insult. Plasminogen activators are hypothesized to impair reactivity to vascular stimuli and produce hyperemia which results in edema causing neuronal cell loss. Dynamic interactions between cerebral blood vessels and neurons thus result in an integrated response to the insult, consistent with the NVU concept. To address this hypothesis, three specific aims will be pursued in newborn pigs: 1. Characterize the relationship between plasminogen activators and cerebral hemodynamics after hypoxia/ischemia, 2. Investigate the role of MAPK as the mechanism by which plasminogen activators control cerebral hemodynamics post insult;Changes in the MAPK isoform expression profile result in impaired cerebral hemodynamics and neuron cell loss. 3. Determine the association between impaired cerebral hemodynamics and histopathology post insult. The closed cranial window technique will be used to measure pial artery diameter and determine CSF plasminogen activator concentration via ELISA. CBF will be determined by the radiolabeled microsphere method. Immunohistochemistry and techniques for detection of plasminogen activator and MAPK expression will be used to achieve an integrated whole animal/molecular perspective on the relationship between plasminogen activators, cerebral hemodynamics, and histopathology.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. 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
  2. pmc RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis
    William M Armstead
    Departments of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA 19104, USA Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Transl Stroke Res 3:114-21. 2012
  3. pmc Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model
    Fang Ji
    Department of Anesthesiology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, China
    Brain Res 1490:95-100. 2013
  4. pmc Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets
    Zhenhong Wang
    Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e41724. 2012
  5. 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
  6. 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
  7. ncbi PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA, l9l04, USA
    Neurocrit Care 20:111-8. 2014
  8. 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
  9. 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
  10. 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

Scientific Experts

  • William Armstead
  • Sherman C Stein
  • Renyu Liu
  • Douglas B Cines
  • Abd Al Roof Higazi
  • Zhenhong Wang
  • John Riley
  • Juan Carlos Murciano
  • Fang Ji
  • Nan Ma
  • Diansan Su
  • Anastasia M Makarova
  • Victoria Stepanova
  • Taher Nassar
  • Rami Abu Fanne
  • Sergei Zaitsev
  • Vladimir R Muzykantov
  • J Willis Kiessling
  • Tatiana V Lebedeva
  • Khalil Bdeir
  • Jing Xue
  • Maria E Carinato
  • Samira Tliba
  • Dirk Spitzer
  • Polianski Vadim
  • Itschak Lamensdorf
  • Sergei Yarovoi
  • Michael Karakoveski
  • M Anna Kowalska
  • Oscar A Marcos-Contreras
  • Mahmud Jammal
  • Bi Sen Ding
  • John P Atkinson
  • Mortimer Poncz
  • Alice Kuo
  • Anwar Rayan

Detail Information

Publications24

  1. 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...
  2. pmc RBC-coupled tPA Prevents Whereas tPA Aggravates JNK MAPK-Mediated Impairment of ATP- and Ca-Sensitive K Channel-Mediated Cerebrovasodilation After Cerebral Photothrombosis
    William M Armstead
    Departments of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA 19104, USA Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Transl Stroke Res 3:114-21. 2012
    ....
  3. pmc Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model
    Fang Ji
    Department of Anesthesiology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, China
    Brain Res 1490:95-100. 2013
    ..The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process...
  4. pmc Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets
    Zhenhong Wang
    Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e41724. 2012
    ..In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway...
  5. 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...
  6. 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
    ....
  7. ncbi PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction
    William M Armstead
    Department of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA, l9l04, USA
    Neurocrit Care 20:111-8. 2014
    ..This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK...
  8. 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...
  9. 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...
  10. 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...
  11. 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...
  12. 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...
  13. pmc Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets
    Diansan Su
    Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA
    Anesth Analg 114:200-4. 2012
    ..We investigated whether pretreatment with salvinorin A, the only natural nonopioid κ receptor agonist, could preserve autoregulation of the pial artery via MAPK...
  14. 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...
  15. 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
    ....
  16. 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
    ....
  17. 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...
  18. 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...
  19. 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...
  20. 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
    ....
  21. 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...
  22. 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...
  23. 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
    ....
  24. pmc Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile
    Juan Carlos Murciano
    Centro Nacional de Investigaciones Cardiovasculares, Madrid Spain
    J Control Release 139:190-6. 2009
    ..This molecular design, capitalizing on unique biological features of the interaction of scuPA with its receptor, provides a promising modality to deliver a pro-drug for prevention of thrombosis...