Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.     

Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL

BACKGROUND: HMG-CoA-reductase-inhibitors (statins) exhibit pleiotropic beneficial effects on the vascular system including induction of endothelial nitric oxide synthase (eNOS) expression which is critical for vasodilation. Recent studies suggest a beneficial effect of statins on cerebral vasoreactivity in patients with cerebral small vessel disease (SVD). CADASIL is a monogenic form of SVD caused by mutations in the Notch3 gene. Treatment options are limited and little is known about the therapeutic role of statins in CADASIL. METHODS: Twenty-four CADASIL subjects were treated with atorvastatin for 8 weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring mean flow velocity (MFV) in the middle cerebral artery was performed at baseline and the end of the treatment period. Vasoreactivity was assessed by hypercapnia and intravenous application of l-Arginine, which is the substrate for eNOS. RESULTS: There was no significant treatment effect on MFV (p=0.5) or cerebral vasoreactivity as assessed by hypercapnia (p=0.5) and intravenous l-Arginine (p=0.4) in the overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2 and l-Arginine-induced vasomotor response (both p<0.05). CONCLUSIONS: Short term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects.     

Anti-Inflammatory Effects of Pravastatin on Helicobacter Pylori-Induced Gastritis in Mice

Pravastatin, an HMG-CoA reductase inhibitor, exerts anti-inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase (eNOS). We investigated the effect of pravastatin on Helicobacter pylori-induced gastritis in mice. Mice with or without H. pylori infection received intraperitoneal pravastatin daily for 1 week. Expression of eNOS mRNA and tumor necrosis factor-α mRNA and myeloperoxidase activity in gastric tissue was determined. Myeloperoxidase activity was reduced in a dose-dependent manner by pravastatin, with activity inhibited by 53.5 and 73.7% at doses of 0.3 and 1 mg/kg, respectively. At a dose of 1 mg/kg, pravastatin reduced the level of tumor necrosis factor-α mRNA by 52.7%, while it did not affect eNOS expression. Pravastatin had no effects on these inflammatory parameters in uninfected mice. Pravastatin did not affect the viability of H. pylori. In conclusion, pravastatin exerts an anti-inflammatory effect on H. pylori-induced gastritis in mice without affecting eNOS expression.     

A pravastatin dose-escalation study in systemic lupus erythematosus

Statin medications have been suggested for widespread use in patients with systemic lupus erythematosus (SLE). We studied the dose effectiveness and tolerability of pravastatin in SLE. We compared 41 SLE subjects in a two-month open-label dose-titration study of pravastatin to 22 SLE controls. Lipids, ALT, CPK, CRP, adverse effects were assessed. Linear mixed models assessed changes in lipids and CRP, comparing pravastatin subjects to controls. After 1 month of pravastatin 10 mg a day, total cholesterol decreased by 16% (±12.1%) and LDL by 24% (±17%), compared with 1.8% (±7.5%) and 2.6% (±8.6%) decreases in controls (P < 0.001). CRP did not decline. Glucocorticoids appeared to decrease pravastatin effectiveness. Serum CPK increased in one subject. Pravastatin reduced LDL and total cholesterol levels approximately the same degree observed in normal individuals, but the effect appeared blunted in those on modest doses of glucocorticoids and those with higher BMI. Supported by NIH grants P60 AR47782, R0149880 and K24 AR052401, the Kirkland Scholar Fellowship, Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award, Rheuminations and a 50th Anniversary Scholars in Medicine Award from Harvard Medical School.     

Lovastatin induces the expression of bradykinin type 2 receptors in cultured human coronary artery endothelial cells

Cardioprotective bradykinin type-2 receptors (BK-2Rs) are downregulated in the myocardial endothelium of both human and rat failing hearts. Statins are cardioprotective drugs that reduce the level of plasma cholesterol but also exert cholesterol-independent pleiotropic effects. Here we examined the effect of lovastatin on BK-2R expression in cultured human coronary artery endothelial cells. The effect of lovastatin on the expression of BK receptors in human coronary artery endothelial cells (HCAECs) was examined by real-time PCR, Western blot analysis and immunocytochemistry. Lovastatin induced a time- and concentration-dependent increase in both BK-2R and BK-1R mRNA expression in the cultured HCAECs. Also, the number of functional BK-2Rs capable of inducing BK-mediated NO production and cGMP signaling was increased in the lovastatin-treated HCAECs. Mevalonate, the direct metabolite of HMG-CoA reductase, reversed the effect of lovastatin. Furthermore, lovastatin inhibited Rho activation and a selective inhibitor of Rho-associated kinases, Y-27632, induced a similar increase in BK-2R expression as lovastatin. In contrast, a specific inhibitor of COX-2, NS398, significantly inhibited the lovastatin-induced expression of BK-2Rs. Here we show for the first time that lovastatin induces the expression of BK-2Rs in cultured human coronary artery endothelial cells through a novel cholesterol-independent pleiotropic mechanism that involves RhoA kinase inhibition and COX-2 activation. Thus, reported beneficial effects of statins in cardiovascular diseases may be partly mediated by an increased expression of cardioprotective BK-2Rs in the endothelial cells of the coronary tree. Moreover, the use of COX-2 inhibitors may affect the level of endothelial BK-2Rs in a negative fashion.     

Effects of rosuvastatin on 3-nitrotyrosine and aortic stiffness in hypercholesterolemia

Background and aimsEarly atherosclerosis is characterized by reduced large artery distensibility, paralleled by an increased peroxynitrite formation and nitration of tyrosine in proteins. The aim of the present study was to investigate the short-term effect of cholesterol lowering with rosuvastatin on 3-nitrotyrosine (3-NT), a marker of peroxynitrite-mediated oxidative stress, and on arterial stiffness.Methods and results71 outpatients with primary hypercholesterolemia were recruited for this randomized open-label intervention study; 35 patients were assigned to 4-week rosuvastatin therapy (10 mg daily) with a low-fat diet, and 36 patients to a low-fat diet only. Within the cohort of 71 hypercholesterolemic patients, there was a significant correlation between cholesterol levels, 3-NT and aortic pulse wave velocity (aPWV), that is a reliable measure of aortic stiffness. Among those patients who received rosuvastatin, significant reductions in plasma cholesterol, 3-NT and aPWV were observed. Reductions in both aPWV and 3-NT levels correlated significantly with the decrease in plasma cholesterol. Reduction of plasma cholesterol was the only independent predictor for reduced arterial stiffness following rosuvastatin therapy.ConclusionCholesterol reduction achieved following short-term rosuvastatin therapy is associated with a decrease in peroxynitrite-mediated oxidative stress and an improvement in large artery distensibility; reduction in arterial stiffness is directly attributable to rosuvastatin-induced cholesterol lowering and not to reduction of plasma 3-NT levels.     

Comparative effects of risedronate,atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats

Objective

The aim of this study was to investigate bone protective effects of risedronate, atorvastatin, raloxifene and clomiphene citrate in ovariectomized rats.

Methods

Our study was conducted on 63 rats at Experimental Research Center of Celal Bayar University. Six-month-old rats were divided into seven groups. There were five drug administered ovariectomized groups, one ovariectomized control group without drug administration and one non-ovariectomized control group without drug administration. Eight weeks postovariectomy, rats were treated with the bisphosphonate risedronate sodium, the statin atorvastatin, the estrogen 17β-estradiol and the selective estrogen receptor modulators (SERMs) raloxifene hydrochloride and clomiphene citrate by gavage daily for 8 weeks. At the end of the study, rats were killed under anesthesia. For densitometric evaluation, left femurs and tibiae were removed. Left femurs were also used to measure bone volume. Right femurs were used for three-point bending test.

Results

Compared to ovariectomized group, femur cortex volume increased significantly in non-ovariectomized group (p = 0.016). Compared to non-ovariectomized group, distal femoral metaphyseal and femur midshaft bone mineral density values were significantly lower in ovariectomized group (p = 0.047). In ovariectomy + atorvastatin group, whole femur and femur midshaft bone mineral density and three-point bending test maximal load values were significantly higher than ovariectomized group (p = 0.049, 0.05, and 0.018). When compared to the ovariectomized group, no significant difference was found with respect to femoral maximum load values in groups treated with risedronate, estrogen, raloxifene and clomiphene (p = 0.602, 0.602, 0.75, and 0.927). In ovariectomy + risedronate group, femur midshaft bone mineral density values were significantly higher than the values in ovariectomized group (p = 0.023). When compared to ovariectomized group, no significant difference was found with respect to femur midshaft bone mineral density values in groups treated with estrogen, raloxifene and clomiphene (p = 0.306, 0.808, and 0.095).

Conclusions

While risedronate sodium prevented the decrease in bone mineral density in ovariectomized rats, atorvastatin maintained mechanical characteristics of bone and also prevented the decrease in bone mineral density as risedronate sodium.     

Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Aβ) levels and the number of Aβ plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Aβ plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.     

Case-control study of statin prevention of mould infections

Invasive mould infections (IMI) are associated with significant morbidity and mortality. In vitro studies have demonstrated that hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have activity against several pathogenic moulds including Zygomycetes and Aspergillus spp. The aim of our study was to determine if statin use is a preventive factor for the development of IMI. This was a retrospective case-control study of 10 United States Veterans Affairs Medical Centers that comprise the Veterans Integrated Service Network (VISN) 16. Cases with IMI and controls were identified from 2001 to 2008. Controls were matched by age, facility, history of transplantation, presence of chronic steroid use and presence of human immunodeficiency virus infection (HIV). Two hundred and thirty-eight patients were included. Independent variables associated with the development of IMI were history of solid malignant tumours (OR 2.63, 1.41-4.87) and hypertension (OR 2.29, 1.13-4.68). Statin use within 3 months of index date was not an independent variable for prevention or development of IMI. No level of exposure to a statin drug appeared to influence the development of infection. This retrospective case-control study suggests that despite evidence of in vitro activity, statins may not decrease risk of IMI. Prospective, controlled trials may be necessary to investigate any potential clinical benefit.     

Cost-effectiveness of intensive atorvastatin therapy in secondary cardiovascular prevention in the United Kingdom, Spain, and Germany, based on the Treating to New Targets study

The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed to predict cardiovascular disease-related events, costs, survival, and quality-adjusted life-years (QALYs). Treatment-specific event probabilities were estimated from the TNT clinical trial. Post-event survival, health-related quality of life, and country-specific medical-care costs were estimated using published sources. Intensive treatment with A80 increased both the per-patient QALYs and corresponding costs of care, when compared to the A10 treatment, in all three countries. The incremental cost per QALY gained was € 9,500, € 21,000, and € 15,000 in the UK, Spain, and Germany, respectively. Intensive A80 treatment is estimated to be cost-effective when compared to A10 treatment in secondary cardiovascular prevention.