Approximately 80-90% of human cerebral ischemic events are caused by thromboembolism. There is a compelling need to develop acute therapeutic interventions for the treatment of stroke. We present preliminary data indicating that atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, extends the therapeutic window of thrombolysis in a rat model of embolic stroke by activation of the PI3- K/Akt signaling pathway. However, the atorvastatin mediated therapeutic effect is independent of eNOS and lipid levels. The goals of this application are to determine the efficacy of statins in combination with thrombolysis for treatment of acute ischemic stroke and to investigate mechanisms underlying the therapeutic effects of atorvastatin as an adjuvant agent to recombinant human tissue plasminogen activator (rht-PA). Our hypotheses are: 1) Treatment of stroke with atorvastatin in combination with rht-PA extends the therapeutic window for acute stroke;2) Atorvastatin activates the PI3-K/Akt signaling transduction pathway in cerebral endothelial cells, which decreases cerebral microvascular thrombosis and blood brain barrier (BBB) leakage by negatively regulating endothelial cell genes that promote thrombogenicity, vascular permeability, and inflammation;3) Activation of the PI3-K/Akt cell survival pathway in neurons by atorvastatin attenuates ischemic neuronal damage exacerbated by delayed treatment of rht-PA. The proposed experiments have been designed to test these hypotheses. Using Magnetic Resonance Imaging (MRI) and 3D laser scanning confocal microscopy (LSCM) techniques, we will first investigate the effects of short-term, high-dose atorvastatin on cerebral vascular patency and integrity including cerebral blood flow (CBF) and BBB leakage, and the neurotoxic effects of tPA. Using laser capture microdissection in combination with real time PCR, Western blot analysis and specific inhibitors which block PI3-K/Akt activation, we will then delve into the mechanisms by which the PI3K/Akt signaling pathway mediates expression of endothelial cell genes involved in thrombosis and BBB leakage, and expression of neuronal genes engaged in the neurotoxic effects of tPA. These studies will lead to a comprehensive understanding of mechanisms underlying the therapeutic effects of statins on extending the window of thrombolysis for acute ischemic stroke and may provide a novel and useful treatment strategy for human ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064766-08
Application #
7600439
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Goldman, Stephen
Project Start
2000-04-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
8
Fiscal Year
2009
Total Cost
$351,988
Indirect Cost
Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Ding, Guang-Liang; Chopp, Michael; Li, Lian et al. (2014) Magnetic Resonance Imaging of Stroke in the Rat. Bo Pu Xue Za Zhi 31:116-132
Wang, Shiyang; Chopp, Michael; Nazem-Zadeh, Mohammad-Reza et al. (2013) Comparison of neurite density measured by MRI and histology after TBI. PLoS One 8:e63511
Li, Lian; Chopp, Michael; Ding, Guang Liang et al. (2012) MRI measurement of angiogenesis and the therapeutic effect of acute marrow stromal cell administration on traumatic brain injury. J Cereb Blood Flow Metab 32:2023-32
Jiang, Quan; Ewing, James R; Chopp, Michael (2012) MRI of blood-brain barrier permeability in cerebral ischemia. Transl Stroke Res 3:56-64
Ding, Guangliang; Jiang, Quan; Li, Lian et al. (2011) Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats. Stroke 42:3537-41
Jiang, Quan; Qu, Changsheng; Chopp, Michael et al. (2011) MRI evaluation of axonal reorganization after bone marrow stromal cell treatment of traumatic brain injury. NMR Biomed 24:1119-28
Wang, L; Chopp, M; Szalad, A et al. (2011) Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience 193:399-410
Zhang, Rui Lan; Chopp, Michael; Roberts, Cindi et al. (2011) Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis. J Cereb Blood Flow Metab 31:614-25
Li, Lian; Jiang, Quan; Qu, Chang Sheng et al. (2011) Transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo MRI study. J Neurotrauma 28:535-45
Liu, Xian Shuang; Chopp, Michael; Zhang, Rui Lan et al. (2011) MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6:e23461

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