This project is designed to investigate the therapeutic effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, on the endogenous neuroplasticity that occurs after traumatic brain injury (TBI) in young adult male Wistar rats. The final goal is to develop a safe and efficacious treatment for TBI, which will reduce neurological defects. Young adult male rats will be subjected to TBI and then treated orally with different doses of simvastatin at various times after TBI. Spatial learning of the rat will be measured using the Morris Water Maze Test. Neurogenesis in the ipsilateral dentate gyrus will be evaluated (Specific Aim 1). The efficacy of simvastatin treatment will be tested and determined based on functional testing and the changes in neurogenesis.
In Specific Aim 2, we will employ immunohistochemical staining, laser cofocal microscopy and enzyme- linked immunosorbent assay (ELISA) to study the dynamic changes of neurogenesis, astrogliogenesis and oligogliogenesis in the dentate gyrus from day 15 to 12 months after TBI. Our observations will provide detailed profiles of the effect of simvastatin treatment on neurogenesis, astrogliogenesis and oligogliogenesis after TBI (A). The microenvironment that regulates neurogenesis in the dentate gyrus will be further investigated after TBI and simvastatin treatment, including angiogenesis, cellular (astrocytes and oligodendrocytes) and molecular (growth factors) regulation (B), as well as intravascular thrombosis and vascular structure (C). These studies will provide insight into the underlying changes in the injured brain induced by statin treatment that contributes to its neurorestorative effect. The ultimate goal of this application is to develop a new treatment for TBI using a statin that will enhance endogenous neuroplasticity in the dentate gyrus, especially neurogenesis, and thereby improving spatial learning after TBI. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052280-02
Application #
7175352
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hicks, Ramona R
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$283,144
Indirect Cost
Name
Henry Ford Health System
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wu, Hongtao; Mahmood, Asim; Qu, Changsheng et al. (2012) Simvastatin attenuates axonal injury after experimental traumatic brain injury and promotes neurite outgrowth of primary cortical neurons. Brain Res 1486:121-30
Wu, Hongtao; Jiang, Hao; Lu, Dunyue et al. (2011) Induction of angiogenesis and modulation of vascular endothelial growth factor receptor-2 by simvastatin after traumatic brain injury. Neurosurgery 68:1363-71; discussion 1371
Wu, Hongtao; Mahmood, Asim; Lu, Dunyue et al. (2010) Attenuation of astrogliosis and modulation of endothelial growth factor receptor in lipid rafts by simvastatin after traumatic brain injury. J Neurosurg 113:591-7
Wu, Hongtao; Jiang, Hao; Lu, Dunyue et al. (2009) Effect of simvastatin on glioma cell proliferation, migration, and apoptosis. Neurosurgery 65:1087-96; discussion 1096-7
Li, Bo; Mahmood, Asim; Lu, Dunyue et al. (2009) Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury. Neurosurgery 65:179-85; discussion 185-6
Mahmood, Asim; Goussev, Anton; Kazmi, Humaira et al. (2009) Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurgery 65:187-91; discussion 191-2
Mahmood, Asim; Goussev, Anton; Lu, Dunyue et al. (2008) Long-lasting benefits after treatment of traumatic brain injury (TBI) in rats with combination therapy of marrow stromal cells (MSCs) and simvastatin. J Neurotrauma 25:1441-7
Xiong, Ye; Mahmood, Asim; Lu, Dunyue et al. (2008) Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Res 1230:247-57
Xiong, Ye; Lu, Dunyue; Qu, Changsheng et al. (2008) Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. J Neurosurg 109:510-21
Wu, Hongtao; Lu, Dunyue; Jiang, Hao et al. (2008) Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma 25:130-9

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