Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood. Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro. Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated. Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs. Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia. 1. Introduction The blood-brain barrier (BBB), a barrier between the central nervous system (CNS) and the systemic circulation, maintains homeostasis within the brain microenvironment. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitutes a “neurovascular unit” that is essential for the health and function of the CNS. Failure of the BBB is a critical event in the progression of several diseases, such as Alzheimer’s disease (AD) [1–4]. BBB breakdown is accompanied by an increase in the trans-endothelial permeability to substances, which can damage the microenvironment of the brain and affect the structure and function of the CNS. Therefore, it is not surprising that strategies have been developed to “repair” the BBB in order to restore normal brain homeostasis and prevent the infiltration of pharmacologically active (noxious) substances into the brain. Cholesterol is one of the most notorious natural risk factors for arteriosclerotic cerebrovascular disease [5, 6]. Mounting evidence suggests that cholesterol also plays a critical role in the early stage of AD [7–9]. Hypercholesterolemia leads to increased BBB leakage, an effect
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