Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells

Jeong, Jin‐Heon; Yum, Kyu Sun; Chang, Joon-Hyuk; Kim, Manho; Ahn, Jin Young; Kim, SangYun; Lapchak, Paul A.; Han, Moon Ku

doi:10.1186/s12883-015-0390-5

Cited by 28 publications

(16 citation statements)

References 31 publications

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“…Our study was designed as a short-term study lasting 2 weeks. In cells, simvastatin exposure leads to immediate dose-related effects [27] , and in our 2-week study, we observed clear effects with a 25% and 50% reduction in plasma and LDL cholesterol concentrations, respectively. In the study by Larsen et al [7] , participants took simvastatin for one year.…”

Section: Discussionsupporting

confidence: 65%

Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial

et al. 2016

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Simvastatin reduces the blood concentration of cholesterol by inhibiting hydroxymethylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, and thereby reduces the risk of cardiovascular disease. In addition, simvastatin treatment leads to a reduction in fluxes in mitochondrial respiratory complexes I and II and might thereby reduce the formation of reactive oxygen species, which have been implicated in the pathogenesis of arteriosclerosis. Therefore, we hypothesized that simvastatin may reduce oxidative stress in humans in vivo.We conducted a randomized, double-blinded, placebo-controlled study in which subjects were treated with either 40 mg of simvastatin or placebo for 14 days. The endpoints were six biomarkers for oxidative stress, which represent intracellular oxidative stress to nucleic acids, lipid peroxidation and plasma antioxidants, that were measured in urine and plasma samples.A total of 40 participants were included, of which 39 completed the trial. The observed differences between simvastatin and placebo groups in the primary outcomes, DNA and RNA oxidation, were small and nonsignificant (p=0.68), specifically, 3% in the simvastatin group compared to 7.1% in the placebo group for DNA oxidation and 7.3% in the simvastatin group compared to 3.4% in the placebo group. The differences in biomarkers related to plasma were not statistically significant between the treatments groups, with the exception of total vitamin E levels, which, as expected, were reduced in parallel with the reduction in plasma cholesterol.In healthy young male volunteers, short-term simvastatin treatment, which considerably reduces cholesterol, does not lead to a clinically relevant reduction in a panel of measures of oxidative stress. Whether simvastatin has effects on oxidative stress in diseased populations, such as diabetes or hemochromatosis, where oxidative stress is prominent, is unknown but seems unlikely.

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Section: Discussionsupporting

confidence: 65%

Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial

et al. 2016

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“…In the current study, 30-day treatment with high-dose Simvastatin resulted in improved clinical outcomes and cognition in mice with Alzheimer's disease. Improvements in apoptosis and cognition were consistent with the results of a recent study, indicating that Simvastatin had regulatory effects on the expression of pathological factors associated with Alzheimer's disease, enabling it to achieve positive therapeutic outcome ( 55 – 57 ).…”

Section: Discussionsupporting

confidence: 88%

Simvastatin inhibits the apoptosis of hippocampal cells in a mouse model of Alzheimer's disease

Song

Fang

et al. 2017

Exp Ther Med

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Alzheimer's disease is associated with cognitive impairments that affect memory and executive functions. Simvastatin is a cholesterol-lowering statin drug that is used to control levels of cholesterol in the blood, particularly in cases of hypercholesterolemia, and may be used in the treatment of aneurysmal subarachnoid hemorrhage. Previous results have indicated that the apoptosis of hippocampal cells may serve a critical role in the progression of Alzheimer's disease. In the present study, it was determined whether Simvastatin inhibited the apoptosis of hippocampal cells in vitro and in vivo. The therapeutic effects of Simvastatin were evaluated in 24-month-old triple-transgenic Alzheimer's disease (3×Tg-AD) mice, and the efficacy of Simvastatin in attenuating memory and cognitive impairment was investigated. Levels of apoptosis-related gene expression in the hippocampus and hippocampal cells of experimental mice were also detected. In addition, neuron excitability was assessed in the functionally relevant brain regions in the hippocampus. The data indicated that Simvastatin significantly suppressed the apoptosis of hippocampal cells in 3×Tg-AD model mice compared with controls (P<0.01). Furthermore, treatment with Simvastatin improved the dementia status of 3×Tg-AD mice, as determined by a learning task in which mice exhibited significantly reduced attention impairment, impulsivity and compulsivity (P<0.01). In addition, results demonstrated that Simvastatin significantly inhibited hippocampal damage and significantly improved neuronal loss in hippocampal structures classically associated with attentional performance when compared with untreated mice (P<0.01). Thus, Simvastatin prevented cognitive impairment by decreasing hippocampal cell apoptosis and improving learning-memory ability. Simvastatin treatment also increased the expression of anti-apoptotic genes and decreased the expression pro-apoptotic genes (P<0.01), which may have been associated with improved motor attention and cognitive competence in 3×Tg-AD mice. Collectively, these preclinical data indicated that Simvastatin was efficient in attenuating memory lapse and hippocampal cell apoptosis in a 3×Tg-AD mouse model. Thus, Simvastatin may be useful in improving the clinical outcome of patients with Alzheimer's disease.

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“… The isoprenoid effect has been attributed to intracellular levels of GGPP and FPP which exhibit opposing effects on cognition . The effect of statins on the isoprenoid levels seems to be dose‐dependent. Low doses of statins preferentially affected the isoprenoid synthesis in cell models , without change in intracellular cholesterol levels, which resulted in decreased Aβ production . The beneficial role of statins on cognition related to the isoprenoid levels has been suggested to be a result of preferentially lowering FPP levels . More specifically, a protective mechanism of statins against glutamate excitotoxicity has been shown to occur by diminishing FPP levels.…”

Section: Medications With Potential Effects On the Brain Cholesterolmentioning

confidence: 99%

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

et al. 2018

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Petek B, Sweden; S€ odersjukhuset, Stockholm, Sweden). Connecting the brain cholesterol and reninangiotensin systems: potential role of statins and RAS-modifying medications in dementia (Review). J Intern Med 2018;284: 620-642.Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications.2 Promotion of oxidative stress by acting on LRX in astroglia [90,91].Brain cholesterol and RAS in dementia / B. Petek et al.

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Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells

Cited by 28 publications

References 31 publications

Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial

Simvastatin and oxidative stress in humans: A randomized, double-blinded, placebo-controlled clinical trial

Simvastatin inhibits the apoptosis of hippocampal cells in a mouse model of Alzheimer's disease

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

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