Spontaneous intracerebral hemorrhage (ICH) affects approximately 75,000 people in the U.S. every year, yet current treatment modalities are limited and most of the patients either die or are left with significant neurological morbidity. Our study is designed to investigate the use of a statin drugs, simvastatin and atorvastatin, after experimental ICH in the rat. Preliminary work in the ICH model as well as in animal models of ischemic stroke and traumatic brain injury has suggested significant improvement in neurological outcome with statin medication, with postulated mechanisms of neurogenesis, angiogenesis, improved blood flow, decreased cerebral ischemia, and growth factor regulation in the region of brain injury. The goals of this revised study are to provide preclinical evidence of the benefit of statin drugs after ICH and to delineate the underlying mechanisms of action so that this type of medication, which is already in widespread clinical use for lowering cholesterol, can have application to patients suffering from ICH. We will compare the effects of simvastatin and atorvastatin on neurological recovery in rats after the autologous blood injection method of ICH using established behavioral measurements after various times of survival. Dose response testing and therapeutic response testing will be obtained to determine the dose and time window of greatest benefit from simvastatin after ICH. The mechanisms by which simvastatin and atorvastatin have their beneficial effects will be studied by measuring neurogenesis and changes in the cellular environment, including markers of new neuronal connections, secretion of growth factors, proliferation of endothelial cells and neovascularization in the perihematoma region. Local effects from the hematoma such as cerebral edema and altered cerebral blood flow will be measured by MR imaging, and the results of statin treatment on these parameters will be calculated. Since there normally is significant loss of cerebral tissue around the ICH in humans and in the animal model, preservation or restoration of the cerebral tissue in the region of the ICH by administration of simvastatin will be measured using both histological and MR imaging techniques. This study will demonstrate the efficacy of statin treatment of ICH and provide insight into the multifaceted restorative effects initiated by statins, with the ultimate objective of translating our pre-clinical studies to the ICH patient. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058581-02
Application #
7501941
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Golanov, Eugene V
Project Start
2007-09-30
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$317,188
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Knight, R A; Nagaraja, T N; Li, L et al. (2016) A Prospective Safety Trial of Atorvastatin Treatment to Assess Rebleeding after Spontaneous Intracerebral Hemorrhage: A Serial MRI Investigation. Austin J Cerebrovasc Dis Stroke 3:
Yang, Dongmei; Knight, Robert A; Han, Yuxia et al. (2013) Statins Protect the Blood Brain Barrier Acutely after Experimental Intracerebral Hemorrhage. J Behav Brain Sci 3:100-106
Yang, Dongmei; Zhang, Jianfeng; Han, Yuxia et al. (2013) Acute Statin Treatment Improves Recovery after Experimental Intracerebral Hemorrhage. World J Neurosci 3:69-75
Yang, Dongmei; Han, Yuxia; Zhang, Jianfeng et al. (2012) Statins Enhance Expression of Growth Factors and Activate the PI3K/Akt-mediated Signaling Pathway after Experimental Intracerebral Hemorrhage. World J Neurosci 2:74-80
Yang, Dongmei; Han, Yuxia; Zhang, Jianfeng et al. (2011) Improvement in recovery after experimental intracerebral hemorrhage using a selective cathepsin B and L inhibitor. J Neurosurg 114:1110-6
Yang, Dongmei; Knight, Robert A; Han, Yuxia et al. (2011) Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study. J Neurosurg 114:1135-42
Seyfried, Donald M; Han, Yuxia; Yang, Dongmei et al. (2010) Localization of bone marrow stromal cells to the injury site after intracerebral hemorrhage in rats. J Neurosurg 112:329-35
Seyfried, D M; Han, Y; Yang, D et al. (2009) Erythropoietin promotes neurological recovery after intracerebral haemorrhage in rats. Int J Stroke 4:250-6
Anagli, John; Han, Yuxia; Stewart, Laura et al. (2009) A novel calpastatin-based inhibitor improves postischemic neurological recovery. Biochem Biophys Res Commun 385:94-9
Karki, Kishor; Knight, Robert A; Han, Yuxia et al. (2009) Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke 40:3384-9

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