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. ? ? ?
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