Matrix metalloproteinase-9 mediated cell death in stroke

Summary

Principal Investigator: ENG LO
Abstract: The NINDS Stroke Program Review Group identified proteolytic pathology in the neurovascular unit as a high priority research area. In this project, we will investigate the mechanisms of matrix metalloproteinase-9 (MMP-9) mediated cell death in cells of the neurovascular unit (cerebral endothelial cells, astrocytes, neurons). We hypothesize that after ischemia, MMP-9 degrades neurovascular matrix and disrupts cell-matrix interactions, thus triggering anoikis-like cell death in endothelium, astrocytes, and neurons. Hence, targeting signaling pathways that mediate MMP-9 dysregulation or initiating a rescue of homeostatic matrix signaling may be viable therapeutic approaches for stroke. To test this hypothesis, we will pursue 3 Specific Aims. In Aim 1, we examine mechanisms of MMP-9 regulation in cell cultures of cerebral endothelial cells, astrocytes, and neurons. Responses to hypoxia/reoxygenation and oxygen-glucose deprivation will be assessed. The roles of three major MAP kinases (ERK, p38, JNK) as signaling mediators will be examined. Endothelial activation via adhesion molecules will be explored as a molecular amplifier. In Aim 2, we test the idea that MMP-9 upregulation disrupts matrix integrin signals and triggers anoikis like death in endothelial cells, astrocytes, and neurons. We will examine the roles of integrin linked kinase (ILK) and Akt cell survival signaling, and try to prevent caspase-mediated cell death by integrin rescue. Pharmacologic inhibitors, RNA interference, and mutant cells lacking MMP-9 or overexpressing the endogenous inhibitor TIMP1 will be used. In Aim 3, we test the hypothesis that targeting MAP kinase pathways in mouse models of focal cerebral ischemia are protective by down regulating ischemic MMP-9 responses. U0126, SB203580, and SP600125 will be used to inhibit ERK, p38 and JNK MAP kinase pathways respectively. To complement these drugs, we will also use molecular approaches involving a JIP1 cDNA to block JNK and a Ras-GRF knockout against ERK. To assess a specific role for MMP-9, experiments will be performed in MMP-9 knockouts, transgenic mice that overexpress the endogenous MMP-9 inhibitor TIMP1, and transgenic mice that express LacZ driven by the MMP-9 promoter. Our lab and others have established MMP-9 as a key extracellular protease that modifies neurovascular homeostasis. These proposed studies should help reveal the mechanisms of MMP-9 mediated cell death in stroke.
Funding Period: 2005-03-01 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Early elevation of serum tumor necrosis factor-α is associated with poor outcome in subarachnoid hemorrhage
    Sherry H Y Chou
    Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02114, USA
    J Investig Med 60:1054-8. 2012
  2. pmc Plasma-type gelsolin is decreased in human blood and cerebrospinal fluid after subarachnoid hemorrhage
    Sherry H Y Chou
    Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02114, USA
    Stroke 42:3624-7. 2011
  3. 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
  4. pmc Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke
    Haihao Zhu
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Cereb Blood Flow Metab 30:1137-46. 2010
  5. pmc Induction of vascular endothelial growth factor and matrix metalloproteinase-9 via CD47 signaling in neurovascular cells
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, MGH East, 149 2401, 13th St, Charlestown, MA 02129, USA
    Neurochem Res 35:1092-7. 2010
  6. 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
  7. pmc Annexin A2: a tissue plasminogen activator amplifier for thrombolytic stroke therapy
    Xiang Fan
    Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Stroke 41:S54-8. 2010
  8. pmc Proteomic temporal profile of human brain endothelium after oxidative stress
    MingMing Ning
    Clinical Proteomics Research Center, Massachusetts General Hospital, Harvard Medial School, Boston, MA, USA
    Stroke 42:37-43. 2011
  9. 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
  10. pmc Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes
    Kazuhide Hayakawa
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
    Glia 58:1007-15. 2010

Scientific Experts

  • C Foerch
  • Ken Arai
  • Josephine M Lok
  • ENG LO
  • MingMing Ning
  • Jianhua Qiu
  • Deepti Navaratna
  • Zhanyang Yu
  • Ru Rong Ji
  • Anna Rosell
  • Anna Devor
  • Xiaoying Wang
  • Norio Fujiwara
  • Shuzhen Guo
  • Changhong Xing
  • Sun Ryung Lee
  • Woo Jean Kim
  • Sherry H Y Chou
  • Bing Qiao Zhao
  • Kazuhide Hayakawa
  • Jianxiang Liu
  • Sophia Wang
  • Brian J Lee
  • Xiang Fan
  • Kyung Pil Park
  • Guang Jin
  • Yoshihiro Murata
  • Elaine Besancon
  • Emiri Tejima
  • Kiyoshi Tsuji
  • Steven K Feske
  • Rachael G Konigsberg
  • Katherine A Hajjar
  • Haihao Zhu
  • Karen L Furie
  • Yong Guang Yang
  • De Maw Chuang
  • Monique F Stins
  • Yasuhiko Kawasaki
  • Young R Kim
  • Kenneth J Rhodes
  • Robert H Scannevin
  • Daniela Bermpohl
  • Bruce R Rosen
  • S R Lee
  • Shu Zhen Guo
  • Hahn Young Kim
  • Seong Ryong Lee
  • Joan Montaner
  • Juli Atherton
  • Rose Du
  • Philip L De Jager
  • Christopher S Ogilvy
  • Terry Chiou
  • Suzanne Simmons
  • David Bauer
  • Po Shun Lee
  • Angel T Som
  • Dana Gallacci
  • Loc Duyen D Pham
  • Jie Lu
  • Song Zhao
  • Klaus van Leyen
  • Ning Liu
  • Yasuhiro Egi
  • Chenggang Zhang
  • Yan Gao
  • Seoul Lee
  • Xunming Ji
  • Ghislain Opdenakker
  • Sunryung Lee
  • David G Nicholls
  • George Dai
  • Ping Heng Tan
  • Zhi Ye Zhuang
  • Yoshi Murata
  • Bing Hao Luo
  • Shoukat Dedhar
  • Jong Yeon Park
  • Gabriel Corfas
  • Kristine Roy
  • Yong Jing Gao
  • Joseph B Mandeville
  • Zhen Zhong Xu
  • Maurits P A van Meer
  • Michael Tymianski
  • H Y Kim
  • Y Murata
  • Michael J Whalen
  • Hyung Hwan Kim

Detail Information

Publications49

  1. pmc Early elevation of serum tumor necrosis factor-α is associated with poor outcome in subarachnoid hemorrhage
    Sherry H Y Chou
    Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02114, USA
    J Investig Med 60:1054-8. 2012
    ..We hypothesize that elevated serum tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) are associated with vasospasm and poor outcome in SAH...
  2. pmc Plasma-type gelsolin is decreased in human blood and cerebrospinal fluid after subarachnoid hemorrhage
    Sherry H Y Chou
    Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02114, USA
    Stroke 42:3624-7. 2011
    ..How these 2 phenomena are related remains unclear. We hypothesize that matrix metalloproteinases (MMPs) mediate the depletion of anti-inflammatory plasma-type gelsolin (pGSN)...
  3. 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...
  4. pmc Annexin A2 combined with low-dose tPA improves thrombolytic therapy in a rat model of focal embolic stroke
    Haihao Zhu
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Cereb Blood Flow Metab 30:1137-46. 2010
    ..As a result, brain hemorrhage and infarction are reduced, and the time window for stroke reperfusion prolonged. Our present findings provide a promising new approach for enhancing tPA-based thrombolytic stroke therapy...
  5. pmc Induction of vascular endothelial growth factor and matrix metalloproteinase-9 via CD47 signaling in neurovascular cells
    Changhong Xing
    Neuroprotection Research Laboratory, Department of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, MGH East, 149 2401, 13th St, Charlestown, MA 02129, USA
    Neurochem Res 35:1092-7. 2010
    ..No changes were detected in pericytes. These findings may provide a potential mechanism for CD47-induced changes in blood-brain barrier homeostasis, and further suggest that CD47 may be a relevant neurovascular target in stroke...
  6. 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...
  7. pmc Annexin A2: a tissue plasminogen activator amplifier for thrombolytic stroke therapy
    Xiang Fan
    Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Stroke 41:S54-8. 2010
    ..Our pilot study using a focal embolic stroke model in rats supports this hypothesis...
  8. pmc Proteomic temporal profile of human brain endothelium after oxidative stress
    MingMing Ning
    Clinical Proteomics Research Center, Massachusetts General Hospital, Harvard Medial School, Boston, MA, USA
    Stroke 42:37-43. 2011
    ..because brain endothelial cells exist at the neurovascular interface, they may serve as cellular reporters of brain dysfunction by releasing biomarkers into the circulation...
  9. 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...
  10. pmc Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes
    Kazuhide Hayakawa
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
    Glia 58:1007-15. 2010
    ..These data suggest a novel pathway by which inflammatory cytokines may enhance the ability of reactive astrocytes to release prorecovery mediators after stroke...
  11. pmc An oligovascular niche: cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells
    Ken Arai
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    J Neurosci 29:4351-5. 2009
    ..These data suggest that a novel oligovascular niche may be important for sustaining oligodendrocyte renewal and homeostasis in mammalian brain...
  12. 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...
  13. 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...
  14. 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...
  15. 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...
  16. pmc Mechanisms and targets for angiogenic therapy after stroke
    Deepti Navaratna
    Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA
    Cell Adh Migr 3:216-23. 2009
    ..A better understanding of the molecular interplay between all these complex pathways may lead to novel therapeutic avenues for tackling this difficult disease...
  17. pmc Neuroglobin-overexpression alters hypoxic response gene expression in primary neuron culture following oxygen glucose deprivation
    Z Yu
    Neuroprotection Research Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital, Program in Neuroscience, Harvard Medical School, 149 13th Street, Room 2411A, Charlestown, MA 02129, USA
    Neuroscience 162:396-403. 2009
    ..Further studies on these gene networks and interactions may lead to better understanding of Ngb in signaling pathways that contribute to neuroprotection...
  18. 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...
  19. 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...
  20. 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...
  21. 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...
  22. pmc Oligovascular signaling in white matter stroke
    Ken Arai
    Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    Biol Pharm Bull 32:1639-44. 2009
    ..A deeper understanding of the mechanisms of oligovascular signaling in normal and pathologic conditions may lead us to new therapeutic targets for stroke and other neurodegenerative diseases...
  23. 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...
  24. pmc CD47 gene knockout protects against transient focal cerebral ischemia in mice
    Guang Jin
    Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02129, USA
    Exp Neurol 217:165-70. 2009
    ..We conclude that CD47 is broadly involved in neuroinflammation, and this integrin-associated-protein plays a role in promoting MMP-9 upregulaton, neutrophil extravasation, brain swelling and progression of acute ischemic brain injury...
  25. pmc Stimulus-induced changes in blood flow and 2-deoxyglucose uptake dissociate in ipsilateral somatosensory cortex
    Anna Devor
    Martinos Center for Biomedical Imaging, Stroke and Neurovascular Regulation Laboratory, Charlestown, Massachusetts 02129, USA
    J Neurosci 28:14347-57. 2008
    ..We propose that other factors, such as neuronal (and glial) release of messenger molecules, might play a dominant role in the regulation of blood flow in vivo in response to a physiological stimulus...
  26. 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
    ....
  27. 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...
  28. 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...
  29. 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
    ....
  30. ncbi TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice
    Daniela Bermpohl
    Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
    J Cereb Blood Flow Metab 27:1806-18. 2007
    ....
  31. ncbi Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke
    Bing Qiao Zhao
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Stroke 38:748-52. 2007
    ..Acute versus chronic protease profiles within the neurovascular unit are likely to underlie critical responses to stroke, therapy, and recovery...
  32. ncbi Effects of apoE isoforms on beta-amyloid-induced matrix metalloproteinase-9 in rat astrocytes
    Shuzhen Guo
    Department of Neurology, Mass General Hospital, Charlestown, MA, USA
    Brain Res 1111:222-6. 2006
    ..Reduction of astrocytic MMP-9 by apoE4 may affect Abeta clearance and promote Abeta deposition in AD...
  33. ncbi Reduction of tissue plasminogen activator-induced matrix metalloproteinase-9 by simvastatin in astrocytes
    Sophia Wang
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Mass 02129, USA
    Stroke 37:1910-2. 2006
    ..Here, we test the idea that statins may directly ameliorate tPA-induced MMP-9 dysregulation...
  34. ncbi Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke
    Seong Ryong Lee
    Department of Neurology and Radiology, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
    J Neurosci 26:3491-5. 2006
    ..These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury...
  35. ncbi Role of matrix metalloproteinases in delayed cortical responses after stroke
    Bing Qiao Zhao
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, MGH East 149 2401, Charlestown, Massachusetts 02129, USA
    Nat Med 12:441-5. 2006
    ..These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery...
  36. ncbi Effect of neuregulin-1 on histopathological and functional outcome after controlled cortical impact in mice
    Josephine Lok
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
    J Neurotrauma 24:1817-22. 2007
    ..Further studies are therefore warranted to more carefully explore molecular mechanisms, dose-responses, and relationships between morphological outcome and long-term recovery...
  37. 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...
  38. 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...
  39. 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...
  40. 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...
  41. 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...
  42. 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...
  43. pmc Neuregulin-1 signaling in brain endothelial cells
    Josephine Lok
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    J Cereb Blood Flow Metab 29:39-43. 2009
    ..These data suggest that NRG1 signaling is functional and cytoprotective in BMECs...
  44. pmc Effects of neuroglobin overexpression on mitochondrial function and oxidative stress following hypoxia/reoxygenation in cultured neurons
    Jianxiang Liu
    Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02129, USA
    J Neurosci Res 87:164-70. 2009
    ..Taken together, these data suggest that Ngb is neuroprotective against hypoxia, in part by improving mitochondria function and decreasing oxidative stress...
  45. ncbi Targeting extracellular matrix proteolysis for hemorrhagic complications of tPA stroke therapy
    Xiaoying Wang
    Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    CNS Neurol Disord Drug Targets 7:235-42. 2008
    ..The data strongly suggest that targeting the extracellular matrix proteolytic imbalance within the neurovascular unit may provide new approaches for improving the safety and efficacy of thrombolytic reperfusion therapy of stroke...
  46. 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...
  47. 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...
  48. ncbi Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia
    Kiyoshi Tsuji
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
    Stroke 36:1954-9. 2005
    ..Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo...