BRAIN CELL APOPTOSIS AFTER INTRACEREBRAL HEMORRHAGE

Summary

Principal Investigator: ENG LO
Abstract: DESCRIPTION: (Verbatim from the Applicant's Abstract) Intracerebral hemorrhage constitutes up to 15 percent of all strokes. Yet, compared to ischemic strokes, the mechanisms of brain cell damage after hemorrhage remain relatively unexplored. Prognosis after hemorrhage is less favorable compared to ischemia. Furthermore, with the risks of hemorrhage associated with thromblytic therapy, it becomes increasingly important to understand the mechanisms of brain damage after hemorrhage. In this proposal, we will use rat and mouse models of intrastriatal hemorrhage to test the overall hypothesis that cell death after hemorrhage is mediated, in large part, by apoptosis. Our preliminary data show that (i) parancymal ischemia accompanying hemorrhage is mild therefore this may favor apoptotic pathways of cell death; (ii) extensive internucleosomal DNA fragmentation occurs in cells surrounding the hemorrhage; (iii) DNA fragmentation post-hemorrhage is reduced by caspase inhibitors; and (iv) pro-apoptotic factors are released into extracellular space after hemorrhage and can be recovered by in vivo microdialysis. Our specific aims are: 1) establish the spatial and temporeal profile of apoptosis after hemorrhage, 2) quantify the levels of parenchymal ischemia adjacent to the hemorrhage and assess the accompanying release of pro-apoptotic factors (Fe2+, thrombin, FasL, TNF) into extracellular space, 3) test the efficacy of caspase inhibitors for reducing brain cell death after hemorrhage, and 4) investigate possible interactions between tissue plasminogen activator (tPA) and hemorrhagic apoptosis. For the 1st aim, we will map morphological, biochemical, and molecular markers of apoptosis after intracerebral hemorrhage. For the 2nd, parenchymal ischemia will be assessed with in vivo MRI methods that measure hemorrhagic progression, blood-brain barrier breakdown, and perfusion deficit. Additionally, we will use in vivo microdialysis to sample extracellular space after hemorrhage and assess the pro-apoptotic activity of Fe2+, thrombin, FasL and TNF with in vitro cultured cells. Experiments will also be performed in TNFR knockout and MnSOD overexpressing transgenic mice. For the third aim, we will characterize the therapeutic window for the caspase inhibitor zVADfmk, compare it with the free radical spin trap alphaPBN, and explore the benefits of combination therapy. Finally, since hemorrhage can be a serious complication of tPA therapy, we will examine as our 4th aim, the effects of tPA on apoptosis in our models. These proposed 3expeiments are expected to synergize with ongoing work in our labs that examine mechanisms that mediate tPA-induced hemorrhage in ischemic stroke (Lo, R01NS37074) and the efficacy of caspase inhibition for cerebral ischemia (Moskowitz, R01NS37141). Results may be used to improve the clinical management and treatment of intracerebral hemorrhage.
Funding Period: 1999-05-01 - 2005-01-31
more information: NIH RePORT

Top Publications

  1. 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
  2. pmc Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity
    Klaus van Leyen
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    J Neurochem 92:824-30. 2005
  3. ncbi A pilot study of normobaric oxygen therapy in acute ischemic stroke
    Aneesh B Singhal
    Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA
    Stroke 36:797-802. 2005
  4. ncbi Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging
    Wellington Pham
    MGH MIT HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA
    Neuroimage 28:287-92. 2005
  5. 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
  6. ncbi Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke
    M Ning
    Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurology 66:1550-5. 2006
  7. ncbi Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage
    Emiri Tejima
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    J Cereb Blood Flow Metab 27:460-8. 2007
  8. ncbi Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study
    Peter J Kelly
    Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland
    Stroke 39:100-4. 2008

Scientific Experts

  • Klaus van Leyen
  • Aneesh Singhal
  • Peter J Kelly
  • Eng H Lo
  • Emiri Tejima
  • Kiyoshi Tsuji
  • Kazuhide Hayakawa
  • Ken Arai
  • Joan Montaner
  • M Ning
  • Bing Qiao Zhao
  • Xiaoying Wang
  • Wellington Pham
  • Brian J Lee
  • Loc Duyen D Pham
  • Angel T Som
  • Shuzhen Guo
  • R Gilberto Gonzalez
  • Anna Rosell
  • A G Sorensen
  • W J Koroshetz
  • K L Furie
  • M Barron
  • E H Lo
  • H Lee
  • M Lederer
  • X Wang
  • M Zhu
  • Bruce Rosen
  • Toshiaki Aoki
  • Paul L Huang
  • Sun Ryung Lee
  • Zdravka Medarova
  • Anna Moore
  • Dmitriy N Atochin

Detail Information

Publications9

  1. 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...
  2. pmc Proteasome inhibition protects HT22 neuronal cells from oxidative glutamate toxicity
    Klaus van Leyen
    Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    J Neurochem 92:824-30. 2005
    ..These findings suggest that caspases can be decoupled from oxidative stress under some conditions, and implicate the ubiquitin/proteasome pathway in neuronal cell death caused by oxidative glutamate toxicity...
  3. ncbi A pilot study of normobaric oxygen therapy in acute ischemic stroke
    Aneesh B Singhal
    Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA
    Stroke 36:797-802. 2005
    ..Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke...
  4. ncbi Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging
    Wellington Pham
    MGH MIT HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA
    Neuroimage 28:287-92. 2005
    ..We conclude that this approach can be used for the delivery of imaging probes and potentially targeted therapeutics across the BBB...
  5. 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...
  6. ncbi Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke
    M Ning
    Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
    Neurology 66:1550-5. 2006
    ..The authors investigated plasma MMP9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP1), in tPA-treated and -untreated stroke patients...
  7. ncbi Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage
    Emiri Tejima
    Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
    J Cereb Blood Flow Metab 27:460-8. 2007
    ....
  8. ncbi Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study
    Peter J Kelly
    Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland
    Stroke 39:100-4. 2008
    ..We aimed to determine the change in plasma F2IP levels over time and relationship with plasma MMP-9 in tPA-treated and tPA-untreated stroke patients...