Abstract

HMG-CoA reductase inhibitors (statins), widely used in the reduction of cholesterol, have pleiotropic effects. Based on robust preliminary data, we seek to develop a novel neuro-restorative treatment of ischemic stroke using statins. These agents, when administered one or more days after stroke, enhance brain plasticity and significantly reduce functional deficits after ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate the cellular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo):
Aim 1 will measure the effects of different doses of statins (simvastatin or atorvastatin) on functional recovery and brain plasticity in old and young adult mice after stroke. The hypothesis to be tested is that treatment of stroke with statins, initiated at one day after stroke onset, improves neurological functional recovery and enhances brain plasticity.
Aim 2 will measure the temporal profile and induction of angiogenesis in ischemic brain treated with statins, the relationship between statin-induced angiogenesis and functional recovery, and potential downstream molecular targets, including synaptic protein expression and the localization of progenitor cells at sites of angiogenesis in ischemic brain. The contribution of VEGF, VEGFR2 and eNOS to statin-induced brain plasticity will be examined by using a specific antibody to VEGFR2 and eNOS knockout mice subjected to stroke and treated with statins, respectively. The underlying hypotheses are that: statins foster functional recovery after stroke by promoting the expression and activation of VEGF/VEGFR2 and eNOS within cerebral tissue; VEGF/VEGFR2 and eNOS instigate brain plasticity via the induction of angiogenesis and provide a microenvironment in brain to further enhance synaptic protein expression and presence of progenitor cells, which augment functional recovery after statin treatment. This study provides a new and highly effective way to treat stroke and may permit translation our finding of restorative therapeutic benefit of statin in experimental stroke to the patient.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047682-03
Application #
7048531
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2004-08-02
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$260,140
Indirect Cost

  Institution

Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Gan, Yan; Liu, Qiang; Wu, Wei et al. (2014) Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A 111:2704-9
Pindolia, Kirit; Li, Hong; Cardwell, Cisley et al. (2014) Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency. Mol Genet Metab 112:49-56
Hernández-Vázquez, A; Wolf, B; Pindolia, K et al. (2013) Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab 110:248-54
Pindolia, Kirit; Chen, Jieli; Cardwell, Cisley et al. (2012) Neurological deficits in mice with profound biotinidase deficiency are associated with demylination and axonal degeneration. Neurobiol Dis 47:428-35
Zacharek, Alex; Shehadah, Amjad; Chen, Jieli et al. (2010) Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke 41:524-30
Chen, Jieli; Zacharek, Alex; Cui, Xu et al. (2010) Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice. J Cereb Blood Flow Metab 30:102-9
Xu, Jian; Liu, Xinfeng; Chen, Jieli et al. (2010) Cell-cell interaction promotes rat marrow stromal cell differentiation into endothelial cell via activation of TACE/TNF-alpha signaling. Cell Transplant 19:43-53
Xu, Jian; Liu, Xinfeng; Chen, Jieli et al. (2009) Simvastatin enhances bone marrow stromal cell differentiation into endothelial cells via notch signaling pathway. Am J Physiol Cell Physiol 296:C535-43
Cui, X; Chopp, M; Zacharek, A et al. (2009) Role of endothelial nitric oxide synthetase in arteriogenesis after stroke in mice. Neuroscience 159:744-50
Chen, Jieli; Cui, Xu; Zacharek, Alex et al. (2009) Niaspan treatment increases tumor necrosis factor-alpha-converting enzyme and promotes arteriogenesis after stroke. J Cereb Blood Flow Metab 29:911-20

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