tPA plus MMP inhibition for combination stroke therapy

Summary

Principal Investigator: ENG LO
Abstract: A major problem with recombinant tissue plasminogen activator (rt-PA) for ischemic stroke is the limited time window for effective therapy and the related complications of cerebral hemorrhage and edema. In response to RFA-HL-05-004, we propose a series of translational animal experiments to test the idea that simultaneously inhibiting matrix metalloproteinases (MMPs) will reduce rt-PA complications, and significantly increase the time window for reperfusion therapy. In Aim 1, we will use a well characterized rat model of embolic (clot-based) focal cerebral ischemia to test the effects of combining rt-PA with the broad spectrum MMP inhibitors BB-94 and minocycline. We will assess the effects of different times of treatment 3-12 h post-ischemia to see whether MMP inhibition can lengthen the time window for effective rt-PA reperfusion. In Aim 2, we will assess the use of immunoliposomes to target our MMP inhibitors to areasof neurovascular damage. Because MMPsalso participate in normal physiology, this form of targeting may be required to optimize clinical use. We will test anti-actin and anti-adhesion molecule (e.g. ICAM-1, E-selectin) immunoliposomes that target cells with damaged membranes and activated ("inflammed") endothelium and astrocytes. In the rat model of embolic clot stroke, we will compare the effects of "naked" BB-94 and minocycline versus immunoliposome- encapsulated compounds. Finally, in Aim 3, we will use in vivo 2-photon imaging to assess rt-PA, MMP inhibition, and vascular leakage within cranial windows in the rat model of embolic stroke. DQ-FITC-gelatin will be infused into the cranial windows, then in vivo 2-photon imaging will be used to mapneurovascular MMP activity overtime. Blood-brain barrier integrity will be assessed using fluorescent dextrans of different sizes. We will compare MMP profiles after saline, rt-PA, or rt-PA plus MMP inhibitors. Over the past 6 years, our lab has accumulated cellular and mechanistic data implicating MMPs in rt-PA thrombolytic complications after stroke. We are now ready to perform the required translational studies derived from our basic findings. If we can obtain proof-of-concept in our animal models that rt-PA plus MMP inhibitors can significantly lengthen the time window for safe and effective reperfusion, this may be an important step forward for combination stroke therapy.
Funding Period: ----------------2006 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators
    Sun Ryung Lee
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurosci Lett 417:1-5. 2007
  2. pmc Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes
    Shuzhen Guo
    Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Stroke 40:652-5. 2009
  3. pmc Role of oxidative stress and caspase 3 in CD47-mediated neuronal cell death
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, MA 02129, USA
    J Neurochem 108:430-6. 2009
  4. pmc Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease
    Shuzhen Guo
    Neuroprotection Research Laboratory, MGH East 149 2401, 13th Street, Charlestown, MA 02129, USA
    Stroke 40:S4-7. 2009
  5. ncbi Mechanisms and markers for hemorrhagic transformation after stroke
    A Rosell
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    Acta Neurochir Suppl 105:173-8. 2008
  6. pmc Interleukin-1beta augments angiogenic responses of murine endothelial progenitor cells in vitro
    Anna Rosell
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Cereb Blood Flow Metab 29:933-43. 2009
  7. pmc Neuroprotective roles and mechanisms of neuroglobin
    Zhanyang Yu
    Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Boston, MA, USA
    Neurol Res 31:122-7. 2009
  8. pmc Neurovascular effects of CD47 signaling: promotion of cell death, inflammation, and suppression of angiogenesis in brain endothelial cells in vitro
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA
    J Neurosci Res 87:2571-7. 2009
  9. pmc Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke
    Ken Arai
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    FEBS J 276:4644-52. 2009
  10. pmc Neurovascular matrix metalloproteinases and the blood-brain barrier
    Ji Hae Seo
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Curr Pharm Des 18:3645-8. 2012

Scientific Experts

  • C Foerch
  • Ru Rong Ji
  • Jianhua Qiu
  • Norio Fujiwara
  • Eng H Lo
  • Shuzhen Guo
  • Xiaoying Wang
  • Ken Arai
  • Josephine Lok
  • Changhong Xing
  • Woo Jean Kim
  • Arne Lauer
  • Anna Rosell
  • E H Lo
  • Brian J Lee
  • Elaine Besancon
  • A Rosell
  • Sun Ryung Lee
  • Ji Hae Seo
  • Frieder Schlunk
  • Elizabeth M Van Cott
  • Kazuhide Hayakawa
  • Helmuth Steinmetz
  • Deepti Navaratna
  • Michael J Whalen
  • Yong Guang Yang
  • Kyung Pil Park
  • Zhanyang Yu
  • Guang Jin
  • Sunryung Lee
  • De Maw Chuang
  • Monique F Stins
  • Klaus van Leyen
  • Young R Kim
  • Aneesh B Singhal
  • Yasuhiko Kawasaki
  • Yoshihiro Murata
  • Y Murata
  • Kenneth J Rhodes
  • Robert H Scannevin
  • S R Lee
  • Hwa Kyoung Shin
  • Kyu Won Kim
  • Elena Schulz
  • Angel T Som
  • Flor A Cianchetti
  • Chris B Schaffer
  • Waltraud Pfeilschifter
  • Loc Duyen D Pham
  • Yasuhiro Egi
  • Karen L Furie
  • MingMing Ning
  • Xunming Ji
  • Xiang Fan
  • Hui Wang
  • Tongrong He
  • Zvonimir S Katusic
  • Miriam Navarro
  • Joan Montaner
  • Ghislain Opdenakker
  • Seoul Lee
  • Kristine Roy
  • Zhen Zhong Xu
  • Michael Tymianski
  • Bing Hao Luo
  • Shoukat Dedhar
  • Ping Heng Tan
  • Yoshi Murata
  • Zhi Ye Zhuang
  • Gabriel Corfas
  • Bruce R Rosen
  • Joseph B Mandeville
  • George Dai
  • Yong Jing Gao
  • Maurits P A van Meer
  • Jong Yeon Park
  • Emiri Tejima
  • P L Huang
  • X Wang
  • Michael A Moskowitz
  • Brian C Magliaro
  • Cenk Ayata
  • Punkaj Gupta
  • C Ayata
  • M A Moskowitz
  • J Lok
  • H Y Kim
  • D Atochin
  • Andrew K Dunn
  • David A Boas

Detail Information

Publications33

  1. ncbi Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators
    Sun Ryung Lee
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurosci Lett 417:1-5. 2007
    ..These data suggest that plasminogen activators may trigger selected pro-inflammatory responses at the neurovascular interface. Whether these effects influence thrombolytic stroke therapy warrants further investigation...
  2. pmc Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes
    Shuzhen Guo
    Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Stroke 40:652-5. 2009
    ..We tested the hypothesis that lithium can promote the expression of growth factors in brain endothelial cells and astrocytes...
  3. pmc Role of oxidative stress and caspase 3 in CD47-mediated neuronal cell death
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, MA 02129, USA
    J Neurochem 108:430-6. 2009
    ..We conclude that CD47 mediates neuronal cell death through caspase-dependent and caspase-independent pathways...
  4. pmc Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease
    Shuzhen Guo
    Neuroprotection Research Laboratory, MGH East 149 2401, 13th Street, Charlestown, MA 02129, USA
    Stroke 40:S4-7. 2009
    ..This minireview surveys recent data that support this basic idea, with examples drawn from experimental models broadly relevant to stroke and neurodegeneration...
  5. ncbi Mechanisms and markers for hemorrhagic transformation after stroke
    A Rosell
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    Acta Neurochir Suppl 105:173-8. 2008
    ....
  6. pmc Interleukin-1beta augments angiogenic responses of murine endothelial progenitor cells in vitro
    Anna Rosell
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Cereb Blood Flow Metab 29:933-43. 2009
    ..Further studies are warranted to assess how interactions between proinflammatory environments and EPC responses may be leveraged to enhance therapeutic angiogenesis...
  7. pmc Neuroprotective roles and mechanisms of neuroglobin
    Zhanyang Yu
    Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Boston, MA, USA
    Neurol Res 31:122-7. 2009
    ..The objectives of this work were to update and summarize recent experimental works on neuroglobin, mainly focus on its neuroprotective effects and the mechanisms...
  8. pmc Neurovascular effects of CD47 signaling: promotion of cell death, inflammation, and suppression of angiogenesis in brain endothelial cells in vitro
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA
    J Neurosci Res 87:2571-7. 2009
    ..We conclude that CD47 signaling can negatively affect the viability and function of cerebral endothelial cells, further supporting the notion that CD47 may be a potential neurovascular target for stroke and brain injury...
  9. pmc Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke
    Ken Arai
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    FEBS J 276:4644-52. 2009
    ..Understanding how neurovascular signals and substrates make the transition from initial injury to angiogenic recovery will be important if we are to find new therapeutic approaches for stroke...
  10. pmc Neurovascular matrix metalloproteinases and the blood-brain barrier
    Ji Hae Seo
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Curr Pharm Des 18:3645-8. 2012
    ..Because BBB perturbations may also occur in neurodegeneration, MMPs and associated neurovascular unit mechanisms may also be potential targets in a broader range of CNS disorders...
  11. pmc Extension of the thrombolytic time window with minocycline in experimental stroke
    Yoshihiro Murata
    Neuroprotection Res Lab, Charlestown, MA 02129, USA
    Stroke 39:3372-7. 2008
    ..In this study, we ask whether minocycline can prevent tPA-associated cerebral hemorrhage and extend the reperfusion window in an experimental stroke model in rats...
  12. pmc Experimental model of warfarin-associated intracerebral hemorrhage
    Christian Foerch
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Masschusetts 02129, USA
    Stroke 39:3397-404. 2008
    ..This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters...
  13. ncbi Cell-cell signaling in the neurovascular unit
    Josephine Lok
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149 2401, Charlestown, MA 02129, USA
    Neurochem Res 32:2032-45. 2007
    ....
  14. pmc Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia
    Hwa Kyoung Shin
    Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    Brain 130:1631-42. 2007
    ..Our data show that normobaric hyperoxia increases tissue O2 delivery, and that novel mechanisms such as CBF augmentation, and suppression of PIDs may afford neuroprotection during hyperoxia...
  15. pmc Intravenous tPA therapy does not worsen acute intracerebral hemorrhage in mice
    Christian Foerch
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 8:e54203. 2013
    ..However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy...
  16. pmc Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia
    S R Lee
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Neuroscience 150:50-7. 2007
    ..Taken together, these data suggest that endogenous tPA contributes to hippocampal injury after cerebral ischemia, and these pathophysiologic pathways may involve links to aberrant activation of caspases and MMPs...
  17. pmc Experimental models, neurovascular mechanisms and translational issues in stroke research
    E H Lo
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA, USA
    Br J Pharmacol 153:S396-405. 2008
    ..Ultimately, both bench-to-bedside and bedside-back-to-bench interactions may be required to overcome the translational hurdles for this challenging disease...
  18. pmc Advances in emerging nondrug therapies for acute stroke 2007
    Aneesh B Singhal
    Neuroprotection Research Laboratory, Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
    Stroke 39:289-91. 2008
  19. pmc Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons
    Shuzhen Guo
    Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
    Proc Natl Acad Sci U S A 105:7582-7. 2008
    ..Targeting these signals of matrix and trophic coupling between endothelium and neurons may provide new therapeutic opportunities for stroke and other CNS disorders...
  20. pmc Functional MRI of delayed chronic lithium treatment in rat focal cerebral ischemia
    Young R Kim
    Athinoula Martinos Center for Biomedical Imaging Massachusetts General Hospital, 149 13th Street, Room 2301, Charlestown, MA 02129, USA
    Stroke 39:439-47. 2008
    ..We further investigated neurohemodynamic aspects of the treatment-associated recovery by assessing the therapeutic efficacy of delayed chronic lithium treatment using functional MRI...
  21. pmc Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain
    Yasuhiko Kawasaki
    Pain Research Center, Department of Anesthesiology, Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Medical Research Building, Room 604, Boston, Massachusetts 02115, USA
    Nat Med 14:331-6. 2008
    ..Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases...
  22. ncbi Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke
    Elaine Besancon
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    Trends Pharmacol Sci 29:268-75. 2008
    ..Further in vivo validation of these pathways could ultimately lead us to new therapeutic targets for stroke, trauma and neurodegeneration...
  23. pmc Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage
    Arne Lauer
    Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
    Circulation 124:1654-62. 2011
    ..Using different experimental models of ICH, this study compared hematoma volume among DE-treated mice, warfarin-treated mice, and controls...
  24. pmc Vascular endothelial growth factor regulates the migration of oligodendrocyte precursor cells
    Kazuhide Hayakawa
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 31:10666-70. 2011
    ..Our findings demonstrate that VEGF-A can induce OPC migration via an ROS- and FAK-dependent mechanism, and suggest a novel role for VEGF-A in white-matter maintenance and homeostasis...
  25. ncbi Effect of normobaric oxygen therapy in a rat model of intracerebral hemorrhage
    Norio Fujiwara
    ACC 729 C, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
    Stroke 42:1469-72. 2011
    ..Normobaric oxygen (NBO) therapy may be neuroprotective in acute ischemic stroke. However, how NBO may affect intracerebral hemorrhage is unclear. We tested NBO in a rat model of striatal intracerebral hemorrhage...
  26. pmc Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage
    Arne Lauer
    Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
    J Cereb Blood Flow Metab 31:1736-42. 2011
    ..Our results suggest that plasmatic coagulation rather than platelet function is the most critical element for preventing hematoma expansion in acute ICH. Future therapeutic strategies may take these findings into account...
  27. pmc High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia
    Jianhua Qiu
    Department of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass 02129, USA
    Stroke 41:2077-82. 2010
    ..This study was intended to investigate the role of extracellular HMGB1 in ischemic stroke by examining the response of the zymogen matrix metalloproteinase-9 (MMP-9) to HMGB1 in vivo and in vitro...
  28. pmc Edaravone, a free radical scavenger, protects components of the neurovascular unit against oxidative stress in vitro
    Brian J Lee
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
    Brain Res 1307:22-7. 2010
    ..Edaravone significantly ameliorated this response. These data suggest that free radical scavengers are effective in all cell types of the neurovascular unit, and should still be considered as a potential therapeutic approach for stroke...
  29. pmc Invited article: searching for oracles? Blood biomarkers in acute stroke
    C Foerch
    Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurology 73:393-9. 2009
    ..Larger clinical trials are warranted to establish the sensitivity and specificity of biomarkers for routine use in clinical stroke...
  30. pmc Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats
    Kyung Pil Park
    Neuroprotection Research Laboratory, MGH East 149 2401 Charlestown, MA 02129, USA
    Stroke 40:2836-42. 2009
    ..Here, we examined the temporal profiles of MMP-9 in blood and brain using a rat model of acute focal cerebral ischemia...
  31. pmc Matrix metalloprotease regulation of neuropathic pain
    Ru Rong Ji
    Pain Research Center, Department of Anesthesiology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Trends Pharmacol Sci 30:336-40. 2009
    ..Inhibition of MMP-9 or MMP-2 might provide a new strategy for the prevention and treatment of neuropathic pain...
  32. pmc Rapid reversal of anticoagulation reduces hemorrhage volume in a mouse model of warfarin-associated intracerebral hemorrhage
    Christian Foerch
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Cereb Blood Flow Metab 29:1015-21. 2009
    ..Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH...
  33. pmc Combination therapy with normobaric oxygen (NBO) plus thrombolysis in experimental ischemic stroke
    Norio Fujiwara
    Neuroprotection Research Laboratory, Departments of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA
    BMC Neurosci 10:79. 2009
    ..NBO was maintained for 3 hours. Infarct volume, brain swelling and hemorrhagic transformation were quantified at 24 hours. Outcome assessments were blinded to therapy...