Ambivalent effects of atorvastatin on angiogenesis, epidermal cell proliferation and tumorgenesis in animal models

A growing body of preclinical data indicates that statins may possess antineoplastic properties; however, some studies have raised the possibility that statins may also have carcinogenic potential. An air pouch model was used for angiogenesis. Single or multiple applications of croton oil on the back of Swiss albino mice with or without initiation by dimethylbenz[a]antheracene [DMBA] were used to evaluate the skin tumorgenesis, ultrastructural and histological alterations. Atorvastatin [orally, 10 mg/kg/day] produced a significant [P<0.05] reduction in angiogenesis. Concurrent administration of mevalonate reversed the antiangiogenic effect of atorvastatin. However, local injection of atorvastatin [200 micro g] into the pouches induced a significant [P<0.5] increase in angiogenesis that was not reversed by co-administration of mevalonate. The disturbance of cell polarity, inflammatory response, thickness of epidermal layer, and mitotic index induced by croton oil were inhibited markedly and dose-dependently [P<0.001] by pre-treatment with atorvastatin. In spite of the strong anti-inflammatory and anti-proliferative effects of atorvastatin on epidermal cell proliferation, it was identified that the same doses of atorvastatin in DMBA-initiated and croton oil-promoted skin tumorgenesis in mice increased the incidence of tumors and their conversion into malignant carcinoma. The reasons for these discrepancies remain unclear, and could be related to ambivalent effects of atorvastatin on angiogenesis or to specific differences in the experimental conditions. It is suggested that the pro-angiogenic effect of the drug, which could be responsible for promotion of skin tumors, is independent of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition that can be mediated directly by atorvastatin

Synthesis of a novel siliconized analog of clofibrate [silafibrate] and comparison of their anti-inflammatory activities

Fibrates, as hypolipidemic drugs known as agonists of peroxisome proliferator-activated receptors, diminish inflammatory responses. Studies have shown that incorporation of a silicon atom into a drug structure improves its pharmacological potency, modifies its selectivity toward a given target, or changes its metabolic rate, in addition to increasing the lipophilicity of the compounds. A siliconized analog of clofibrate, ethyl-2-methyl-2-[4-[trimethylsilyl]phenoxy]propionate was synthesized, whereby the chlorine atom in the phenoxy ring was replaced by a trimethylsilyl group. The anti-inflammatory effects of the siliconized analog [silafibrate] were evaluated in an air-pouch model of inflammation and compared with those of clofibrate. Oral administration of both drugs produced a significant anti-inflammatory action by reducing carrageenan induced pouch leukocyte recruitment, exudates production, and granulated tissue weight. The silicon isostere of clofibrate has improved anti-inflammatory properties

Vascular dysfunction in short-term hypercholesterolemia despite the absence of atherosclerotic lesions

The atherosclerotic effect of hypercholesterolemia on the vascular function is well-known. However, limited studies were done on the effect of hypercholesterolemia without atherosclerotic lesion on thq vascular compliance. The aim of this study was to investigate the effects of hyperlipidemia induced by cholesterol rich diet on vessel function in isolated rat aorta in the absence of atherosclerotic lesion. Male wistar rats were randomly divided into 3 groups of 6 animals in each. The rats in normal control group were fed a standard laboratory diet and two other groups were fed a high fat diet for 36 days. A group of high fat fed rats was treated orally with Lovastatin started at day of 16 and continued for last 20 days of the experimental period. At the end of the experiment, inferior vena cava blood was collected to measure the lipid levels and the thoracic aorta was excised and used for isolated vessel preparation and histological study. Results: The results of this study indicated that high-cholesterol diet significantly increased total cholesterol and LDL levels in serum [p<0.001]. The increase in the serum levels of cholesterol was associated with a profound reduction of endothelium dependent vasodilatation of the thoracic aorta. However, in histopathological study no atherosclerotic lesion was observed. Short-term treatment by Lovastatin [10 mg/kg/day] produced a significant reduction[p<0.05] in the level of total cholesterol and LDL. The endothelium-dependent vasodilatation was improved significantly [P<0.01] by Lovastatin as an anti-hyperlipidemic drug. Hypercholesterolemia is associated with endothelial dysfunction in aorta, despite the absence of atherosclerotic lesions

impact of gender on the inflammatory parameters and angiogenesis in the rat air pouch model of inflammation

Air pouch is a well-established inflammatory model in which fluid extravasations; leukocyte migration, angiogenesis and other parameters involved in the inflammatory response can be measured. In this study, the influence of gender on inflammatory parameters has been examined in the air pouch model. To induce air pouch, adult male and female Wistar rats were anesthetized, then 20 ml and 10 ml of sterile air were injected subcutaneously on the back on day 0 and day 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 6 and 72 hr, the rats were sacrificed, pouch fluid was collected in order to determine exudates volume and the accumulated cells were counted using a hemocytometer. Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using hemoglobin kit. Analysis of our data demonstrated a sexually dimorphic pattern in inflammation parameters both in acute and chronic forms [P<0.05]. The value of angiogenesis in the air pouch model in male rat was higher than that female rats [P<0.001]. The degree of inflammation and angiogenesis induced in Wistar rat air pouch model is gender-dependent, suggesting that gender may be a key consideration in the design of inflammation experiments

Biphasic effects of atorvastatin on inflammation

Statins have been shown to exert "pleiotropic effects" independent of their cholesterol lowering actions that include anti-inflammatory properties. We show in this study that atorvastatin dependent on the way of administration may exert anti- or pro- inflammation effects. Carrageenan-induced rat paw edema and mouse air-pouch as inflammatory models were used in this study. Animals were received statins orally prior to induction of inflammation by injection of carrageenan into rat paw or the pouch. The local effect of atorvastatin was determined by injection of the drug into the pouch. Oral administration of statins reduced both the maximal edema response and neutrophils infiltration in the inflammation zone. Lovastatin had the lowest and atorvastatin had the greatest effects. Also, in the mouse air-pouch model oral treatment by atorvastatin produced a very significant [p < 0.0001] reduction in carrageenan-induced pouch leukocyte recruitment and exudates production. Concurrent administration of mevalonate revers ed the anti-inflammatory effect of atorvastatin. However, local injection of atorvastatin into the pouch induced a dose depend and significant increase in leukocyte recruitment into the pouch that was not reversed by co-administration of mevalonate. This study shows that atorvastatin dependent on the way of administration has both pro- and anti- inflammatory properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of HMG CoA reductase inhibition and can be mediated directly by atorvastatin

Screening of extracts and fractions from aerial parts of stachys schtschegleevii sosn. for anti-inflammatory activities

Stachys schtschegleevii Sosn. is a native plant widely distributed in Iran and belongs to family of Lamiaceae and genus of Stachys. The plant is used in Iranian folk medicine in infective, rheumatic and other inflammatory disorders. In the present study the anti-inflammatory properties of different extracts and components isolated from aerial parts of Stachys schtschegleevii Sosn. were investigated. Intraperitoneal injection of hydroalcoholic extract 60 min before the induction of carrageenan-induced rat paw oedema significantly reduced the maximal oedema response attained during 4 hr and the total oedema response. A low dose of chloroform extract [100 mg/kg] caused significant inhibition of the carrageenan-induced inflammation, whereas a high dose of 400 mg/kg produced a pro-inflammatory response. One of the ethyl acetate extract caused a potent and dose-related inhibition of inflammation. This extract was fractionated into 11 major fractions according to increasing polarity of solvent mixtures. These results suggest that the hydroalcoholic extract of aerial parts of Stachys schtschegleevii attenuate the inflammatory response. The compounds in different fractions have also been identified to exhibit anti-inflammatory activity through thin layer chromagoraphy