-
[show abstract]
[hide abstract]
ABSTRACT: Abstract Background: Population-based data on serum adiponectin levels, an adipocytokine secreted from adipose tissue, are lacking, particularly across race-ethnic groups. Studies have suggested an inverse association between adiponectin and vascular risk factors, but data are limited and inconsistent. We examined the cross-sectional association between adiponectin, vascular risk factors and race-ethnicity in the population-based Northern Manhattan Study (NOMAS). Methods: Blood samples, anthropomorphics, and vascular risk factors were collected at baseline. Multivariable linear regression analysis was conducted with log-transformed adiponectin as the dependent variable. Results: Adiponectin was measured among 2900 participants (age 69±10 years, body mass index (BMI) 28.0±5.6, 37% male, 21% white, 53% Hispanic, 24% black). The mean adiponectin was 11.4±6.2 μg/mL (median=9.8, range=2.1-53.3). After multivariable adjustment, adiponectin levels were greatest among whites, followed by Hispanics, and lowest among blacks. Lower adiponectin levels were observed in participants with the following characteristics: Male, former smoking, hypertension, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), metabolic syndrome, moderate alcohol use, elevated waist circumference, BMI, estimated glomerular filtration rate (eGFR), triglycerides, low-density lipoprotein cholesterol (LDL-C), lower high-density lipoprotein cholesterol (HDL-C), and younger age. Obesity was a stronger risk factor for decreased adiponectin among blacks than among whites or Hispanics. The associations for several vascular risk factors, including hypertension, triglycerides, and low HDL-C, with low adiponectin were stronger among individuals who were not obese than among those who were obese. Conclusions: Adiponectin levels were lower among blacks and Hispanics and among those with various vascular risk factors, and greater with older age. The association between BMI and adiponectin varied across race-ethnic groups. Investigation of whether differences in body fat distribution may explain race-ethnic differences in adiponectin is needed.
Metabolic syndrome and related disorders 11/2012;
-
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin is an insulin-sensitizing plasma protein expressed in adipose tissue and suggested to play a role in atherosclerosis and cardiovascular disease. Data are lacking on the relationship between adiponectin and carotid intima-media thickness (IMT) in ethnically heterogeneous populations. We examined the relationship between adiponectin and IMT, a marker of atherosclerosis, in a multiethnic cohort study of stroke risk factors.
Participants were from the Northern Manhattan Study (N=1522, mean age 66±9 years, 60% female, 20% black, 18% white, 60% Hispanic). Adiponectin was measured from baseline plasma samples and IMT was assessed by high-resolution B-mode carotid ultrasound. Regression models were used to examine the association between adiponectin, assessed continuously and in quartiles, and IMT controlling for demographics and vascular risk factors.
The mean adiponectin level was 10.3±5.2 μg/mL (median, 9.2 μg/mL; range, 2.3-53.3 μg/mL), and the mean IMT was 0.91±0.08 mm. Adiponectin was inversely associated with IMT, even after controlling for demographics and vascular risk factors. Individuals in the first quartile of adiponectin had mean IMT that was on average 0.02 mm greater than those in the top quartile. The relationship between adiponectin and IMT appeared to be stronger among those with diabetes.
Our findings suggest that low adiponectin is associated with increased IMT in a multiethnic cohort and support a protective role for adiponectin in atherosclerosis.
Stroke 12/2011; 43(4):1123-5. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The association between C-reactive protein (CRP) and future cardiovascular risk has been of particular interest during recent years. Oxidized low-density lipoprotein (ox-LDL) is another marker linking the immune system with the atherogenic process. The aim of this study was to examine whether ox-LDL and CRP were associated with endothelial function in peripheral resistance arteries. Twenty-five men with a previous hospital-diagnosed myocardial infarction were enrolled in the study. The exclusion criterion was a history of diabetes mellitus. IgG and IgM autoantibodies to malonyldialdehyde low-density lipoprotein (MDA-LDL) and high-sensitivity CRP (hs-CRP) were measured. Flow-mediated dilatation was measured in isolated resistance arteries from subcutaneous fat biopsies. Endothelial function test reflecting the maximum vessel dilatation in male subjects was inversely related to MDA-LDL IgG autoantibody levels (r = -0.6 and P = 0.003). Comparison of hs-CRP levels and of maximum vessel dilatation in males revealed also an inverse relation (r= -0.4 and P = 0.04). In conclusion, a clear correlation exists between flow-mediated dilatation in subcutaneous resistance arteries and plasma levels of MDA-LDL IgG autoantibody and CRP in male patients with coronary heart disease.
Heart and Vessels 04/2009; 24(2):90-5. · 2.05 Impact Factor
-
Anna Poggesi,
Giovanni Pracucci,
Hugues Chabriat,
Timo Erkinjuntti,
Franz Fazekas,
Ana Verdelho,
Michael Hennerici,
Peter Langhorne,
John O'Brien,
Philip Scheltens,
Marieke C Visser, Milita Crisby,
Gunhild Waldemar,
Anders Wallin,
Domenico Inzitari,
Leonardo Pantoni
[show abstract]
[hide abstract]
ABSTRACT: To investigate, in a cohort of nondisabled elderly people, the association between urinary complaints and severity of age-related white matter changes (ARWMC).
Cross-sectional data analysis from a longitudinal multinational study.
The Leukoaraiosis And DISability Study, assessing ARWMC as an independent predictor of the transition from functional autonomy to disability in elderly subjects.
Six hundred thirty-nine subjects (288 men, 351 women, mean age 74.1+/-5.0) with magnetic resonance imaging (MRI)-detected ARWMC of different severity.
ARWMC severity was graded on MRI as mild, moderate, and severe (Fazekas scale). MRI assessment also included ARWMC volumetric analysis and the count of infarcts. Urinary complaints (nocturia, urinary frequency, urgency, incontinence) were recorded based on subjects' answers to four questions.
In comparing the three ARWMC severity groups, there was a significant difference only in prevalence of urgency, with 16% of subjects in the mild severity group, 17% in the moderate severity group, and 25% in the severe group (P=.03). Adjusting for age, sex, lacunar and nonlacunar infarcts, diabetes mellitus, and use of diuretics, severe ARWMC retained an independent effect in the association with urinary urgency (odds ratio=1.74, 95% confidence interval=1.04-2.90, severe vs mild group). Subjects with urinary urgency also had higher ARWMC volumes (25.2, vs 20.4 mm(3) in those without urinary urgency; P<.001). Urgency was confirmed to be associated with the severe degree of ARWMC, irrespective of complaints of memory, gait disturbances, or history of depression.
In a cohort of nondisabled elderly people, severe ARWMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain.
Journal of the American Geriatrics Society 08/2008; 56(9):1638-43. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.
Neurochemistry International 06/2007; 50(6):800-6. · 2.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The influence of a high cholesterol (HC) diet on brain pathology is being recognized increasingly and is of immense interest. Previous findings from our laboratory demonstrated that a high cholesterol diet increases gliosis, astrocytic reactivity and neuroinflammation in both wild type (WT) and apolipoprotein knockout (ApoE-/-) mice. In the present study, we analyzed whether this increase in astrocytic reactivity, monitored by the number of cells in the hippocampus labelled with glial fibrillary acidic protein (GFAP), could be reduced by the use of rosuvastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. Furthermore, we studied the effect of rosuvastatin on changes in lipoprotein levels and weight gain, and their correlation to gliosis, in mice fed a high cholesterol diet. A significant increase in weight, total-cholesterol (TC) and low-density lipoprotein (LDL) levels were observed in WT and ApoE-/- mice on a HC diet. The number of GFAP labelled cells was found to be significantly increased in mice on a HC diet and reduced in rosuvastatin-treated WT and ApoE-/- mice on a HC diet. A significant reduction of weight, total-cholesterol and LDL levels was observed in rosuvastatin-treated WTHC mice. Significant correlations were found between changes in body weight, GFAP labelled cells and plasma total-cholesterol levels in WT and ApoE-/- mice. However, the correlations were found to be weaker for the GFAP labelled cells in the ApoE-/- mice. The results indicate that the observed reduction of gliosis by rosuvastatin treatment may be due to mechanisms that are independent of its lipid-lowering effect.
Neuroscience Letters 06/2007; 419(1):68-73. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Our objective was to assess vascular endothelial function and morphology in resistance vasculature from healthy pre- and postmenopausal women in vitro and to determine potential mechanisms of vascular protection by estrogenic compounds.
Arteries (approximately 220 microm) were dissected from sc fat biopsies obtained from healthy premenopausal and postmenopausal women. Flow-mediated dilatation, agonist-induced endothelium-dependent and -independent relaxation, and myogenic responses to changes in intraluminal pressure were evaluated before and after incubation (3 h) with 17beta-estradiol, propyl pyrazole triol [a selective estrogen receptor-alpha (ERalpha) agonist], raloxifene (a second-generation selective ER modulator), and the phytoestrogen genistein, using pressure myography technique. In addition, endothelial morphology was assessed in arteries from pre- and postmenopausal women, and distribution of ERs within the artery wall from postmenopausal women was evaluated.
Functional and morphological disturbances of endothelial function were observed in small arteries from postmenopausal women. Incubation with 17beta-estradiol improved postmenopausal resistance artery function, an effect mimicked by propyl pyrazole triol but not raloxifene or genistein. Immunohistochemical staining revealed similar expression of ERalpha and ERbeta in the smooth muscle of arteries from postmenopausal women; however, ERalpha was dominant in endothelium.
The resistance arteries from postmenopausal women show functional and morphological abnormalities. ERalpha may contribute to vascular protection by estrogens in the peripheral resistance circulation in postmenopausal women. Selective ERalpha agonists warrant further investigation as therapeutic agents for prevention of cardiovascular disease in postmenopausal women.
Journal of Clinical Endocrinology & Metabolism 12/2005; 90(11):6113-22. · 6.50 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We analysed the effects of high cholesterol (HC) intake and reduced apolipoprotein E (apoE) activity on tau phosphorylation and on the activities of the major tau kinases and phosphatases in brains from wild-type and apoE-knockout (apoEKO) mice. We show that HC diet potently induced intraneuronal accumulation of hyperphosphorylated tau in apoEKO mice, as well as upregulation of several tau kinases, without affecting tau phosphatases. Our results suggest an interaction between dietary and genetic factors in the development of tauopathies, which can be relevant in humans, where the apoE4 isoform could have a lack of function as compared to other isoforms.
FEBS Letters 12/2005; 579(28):6411-6. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High serum cholesterol level has been shown as one of the risk factors for Alzheimer's disease (AD), and epidemiological studies indicate that treatment with cholesterol-lowering substances, statins, may provide protection against AD. An acute-phase reaction and inflammation, with increased levels of proinflammatory cytokines, are well known in the AD brain. Notably, there is evidence for antiinflammatory activities of statins, such as reduction in proinflammatory cytokines. Consequently, it is of interest to analyze the effects of statins on microglia, the main source of inflammatory factors in the brain, such as in AD. The aims of this study were to determine the effects of statins (atorvastatin and simvastatin) on microglial cells with regard to the secretion of the inflammatory cytokine interleukin-6 (IL-6) and cell viability after activation of the cells with bacterial lipopolysaccharides (LPS) or beta-amyloid1-40 (Abeta1-40) and in unstimulated cells. Cells of the human microglial cell line CHME-3 and primary cultures of rat neonatal cortical microglia were used. Incubation with LPS or Abeta1-40 induced secretion of IL-6, and Abeta1-40, but not LPS, reduced cell viability. Both atorvastatin and simvastatin reduced the basal secretion of IL-6 and the cell viability of the microglia, but only atorvastatin reduced LPS- and Abeta1-40-induced IL-6 secretion. Both statins potentiated the Abeta1-40-induced reduction in cell viability. The data indicate the importance of also considering the microglial responses to statins in evaluation of their effects in AD and other neurodegenerative disorders with an inflammatory component.
Journal of Neuroscience Research 11/2005; 82(1):10-9. · 2.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to have anticancer effects in many models. We have investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, while mRNA levels were unchanged. Furthermore, pravastatin was found to induce phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to active Mdm2 and has been shown to increase its ubiquitin ligase activity and lead to increased p53 degradation. Our data show that statins attenuated the p53 response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil and benzo(a)pyrene. Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 degradation. The induction of p53 responsive genes and apoptosis was attenuated. Mdm2 and p53 were also studied in vivo in rat liver employing immunohistochemistry, and it was found that constitutive Mdm2 expression was changed in livers of pravastatin-treated rats. We also show that the p53 response to a challenging dose of diethylnitrosamine was attenuated in hepatocytes in situ and in primary cultures of hepatocytes by pravastatin pretreatment. Taken together, these data indicate that statins induce an mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the duration and intensity of the p53 response to DNA damage in hepatocytes.
The FASEB Journal 04/2005; 19(3):476-8. · 5.71 Impact Factor
-
Milita Crisby
[show abstract]
[hide abstract]
ABSTRACT: Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.
Timely topics in medicine. Cardiovascular diseases 02/2005; 9:E3.
-
[show abstract]
[hide abstract]
ABSTRACT: An increasing number of studies suggest that disturbances in cholesterol homeostasis may promote the formation and deposition of beta-amyloid (A beta) and the progression of Alzheimer's disease (AD). In this paper, we have analyzed the effect of the lipid-lowering compound rosuvastatin on apoptosis and caspase-3 activity in human neuroblastoma SH-SY5Y cells. Exposure of SH-SY5Y cells to A beta(1-42) alone resulted in a significantly increased caspase-3 activity approximately by 35% (135+/-15%, p<0.05), and decreased alpha-secretase activity by 34% (67.4+/-2.7%, p<0.001) compared to the controls (100+/-18.1%). Rosuvastatin alone decreased caspase-3 activity by 15% (85.3+/-1.5%, p<0.0005) compared to the controls and by 50% to cells exposed to A beta alone (p<0.00005). Cells exposed to rosuvastatin alone had a higher alpha-secretase activity compared to cells exposed to A beta (76.4+/-23.8%, n.s.) but a slightly lower activity compared to the controls (n.s.). Pre-treatment of SY-SY5Y cells with rosuvastatin prior to incubation with A beta(1-42) resulted in decreased caspase-3 activity by approximately 15% compared to the controls and by approximately 48% (86.8+/-16.9%, p<0.05) compared to cells treated with A beta(1-42) alone. Also, alpha-secretase activity was increased by approximately 50% compared to the controls and by 84% (151.3+/-10.1%, p<0.05), compared to cells treated with A beta(1-42) alone. Mevalonate abrogated the effect of rosuvastatin in vitro. To our knowledge, this is the first study demonstrating that the hydrophilic compound rosuvastatin decreases caspase-3 activity and increases alpha-secretase activity in human neuroblastoma SH-SY5Y cells exposed to A beta in vitro. These effects are essential for modulation of the amyloidogenic pathway and mediators of apoptosis in AD.
Neuroscience Letters 11/2004; 371(2-3):209-14. · 2.11 Impact Factor
-
Milita Crisby
Stroke 10/2003; 34(9):2302-3. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer's disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer's peptide (Abeta(1-42))-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1mg x ml(-1)) for 24h were stimulated with 5 microM of freshly dissolved Abeta(1-42) for the next 24h. The pre-treatment of cells with pravastatin diminished the capacity of Abeta to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Abeta(1-42) separately increased PPARgamma activity, the combination of Abeta(1-42) and pravastatin resulted in no effect on PPARgamma expression. These data indicate that soluble forms of Abeta(1-42), which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin.
Pharmacological Research 03/2003; 47(2):119-26. · 4.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 microM) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 microg ml(-1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins.
Pharmacological Research 03/2002; 45(2):147-54. · 4.44 Impact Factor
-
Milita Crisby
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological studies indicate that the risk of first ever stroke is strongly related to age. Based on the NASCET and ECST results, carotid endarterectomy (CEA) is a well-established indication for the prevention of ischemic stroke in patients with 70-99% symptomatic internal carotid artery (ICA) stenosis and in selective cases with moderate stenosis (50-69%). A recent analysis of data from the NASCET group, clearly demonstrates that elderly patients (age > 75 years) with symptomatic ICA stenosis benefit more from CEA compared to younger patients. However, the NASCET collaborators point out that the greater benefits achieved in patients older than 75 years compared to other age groups in the trial depends on the fact that CEA was performed on the elderly having a higher risk of ipsilateral ischemic stroke if treated medically and the lowest surgical risk. In order to obtain the treatment benefit reported, operation performed by skilled surgeons and meticulous medical screening of the elderly patients is recommended to exclude life-threatening conditions.
Lakartidningen 02/2002; 99(1-2):27-8.
-
[show abstract]
[hide abstract]
ABSTRACT: Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 μ M) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 μ g ml−1) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR γ). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF κ B) expression and reduced uptake of125I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR γ levels and abolished NF κ B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- α). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR γ and NFκ B in the modulation of the inflammatory processes by statins.
Pharmacological Research.
-
[show abstract]
[hide abstract]
ABSTRACT: Vascular risk factors such as hypertension and hypercholesterolemia during midlife increase the risk for Alzheimer's disease (AD). Treatment of hypercholesterolemia and other vascular risk factors may have great implications in the prevention of AD. Recent findings illustrate that the sterol metabolism in the brain is an active process, well controlled and regulated by 24-hydroxylase, an enzyme that is uniquely expressed in the brain. The use of statins in ischemic heart disease (IHD) has proven to be a phenomenal advance in pharmacological disease prevention and treatment. A growing body of evidence, suggest that statins exhibit additional benefits that are independent of their cholesterol-lowering actions. Statin treatment has also considerable effect in prevention of ischemic stroke. In animal models of ischemic stroke, statins have proven to reduce infarct size through up-regulation of endothelial nitric oxide synthases. Data from recent observational studies have revealed a potential role for statins in prevention of AD. The following review comments the processes leading to dementia including the involvement of cholesterol regulation, cerebral circulation and inflammation in development of dementia. The mechanisms by which statins may be beneficial in controlling these processes is discussed.
Alzheimer Disease and Associated Disorders 16(3):131-6. · 2.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: An increasing number of studies suggest that disturbances in cholesterol homeostasis may promote the formation and deposition of beta-amyloid (Aβ) and the progression of Alzheimer's disease (AD). In this paper, we have analyzed the effect of the lipid-lowering compound rosuvastatin on apoptosis and caspase-3 activity in human neuroblastoma SH-SY5Y cells. Exposure of SH-SY5Y cells to Aβ1–42 alone resulted in a significantly increased caspase-3 activity approximately by 35% (135 ± 15%, p < 0.05), and decreased α-secretase activity by 34% (67.4 ± 2.7%, p < 0.001) compared to the controls (100 ± 18.1%). Rosuvastatin alone decreased caspase-3 activity by 15% (85.3 ± 1.5%, p < 0.0005) compared to the controls and by 50% to cells exposed to Aβ alone (p < 0.00005). Cells exposed to rosuvastatin alone had a higher α-secretase activity compared to cells exposed to Aβ (76.4 ± 23.8%, n.s.) but a slightly lower activity compared to the controls (n.s.).Pre-treatment of SY-SY5Y cells with rosuvastatin prior to incubation with Aβ1–42 resulted in decreased caspase-3 activity by ∼15% compared to the controls and by ∼48% (86.8 ± 16.9%, p < 0.05) compared to cells treated with Aβ1–42 alone. Also, α-secretase activity was increased by approximately 50% compared to the controls and by 84% (151.3 ± 10.1%, p < 0.05), compared to cells treated with Aβ1–42 alone. Mevalonate abrogated the effect of rosuvastatin in vitro.To our knowledge, this is the first study demonstrating that the hydrophilic compound rosuvastatin decreases caspase-3 activity and increases α-secretase activity in human neuroblastoma SH-SY5Y cells exposed to Aβ in vitro. These effects are essential for modulation of the amyloidogenic pathway and mediators of apoptosis in AD.
Neuroscience Letters.
-
Lakartidningen 105(48-49):3541-3.
