Simvastatin reverses cyclosporin A-induced endothelial damage in rats: lipid-lowering-dependent and -independent effects

Cydosporin A [CyA] is the immunosuppressant most frequently used in transplant surgery and in the management of autoimmune diseases. CyA-induced oxidative stress together with dyslipidemia have been implicated in the pathogenesis of vascular dysfunction associating CyA therapy. The present study investigated the possible protective effect of simvastatin, a lipid-lowering drug with potent antioxidant properties, against CyA-induced endothelial damage in male rats. Eighteen male Wistar rats were used. They were divided into 3 groups: control, CyA and CyA + simvastatin. In the control group, rats were administered the vehicle, olive oil; in the CyA group, rats were administered CyA [20 mg/kg/day, s.c. for 14 days] and in the CyA+simvastatin group, rats were co-administered simvastatin [2.5 mg/kg/day, s.c. for 14 days] and CyA. Administration of CyA [20 mg/kg/day, s.c. for 14 days] in male rats resulted in a significant increase in the lipid peroxidation product, malondialdehyde [MDA], and a significant decrease in superoxide dismutase [SOD] activity in plasma. CyA treatment was also associated with a significant increase in plasma nitrite level as well as an elevation in plasma cholesterol, triglycerides [TGs], low density lipoproteins [LDL] and a reduction in high density lipoproteins [HDL] levels. CyA-induced vascular dysfunction was further confirmed by the attenuation of endothelium-dependent relaxations produced by carbachol in rat isolated aortic rings. Co-administration of simvastatin [2.5 mg/kg/day, s.c. for 14 days] with CyA significantly reversed the deleterious biochemical and functional vascular effects that accompanied CyA treatment. The present study provides good evidence that both oxidative stress and dyslipidemia underlie the CyA-induced vascular damage, an effect that could be reversed by simvastatin co-administration

Effect of mastic gum, and vitamin e on ethanol/hcl-induced gastric ulcers in rats

Gastric ulcers were induced in the rat stomach by oral administration of ethanol/HCl [150 mM HC1 in 60% ethanol, 1 ml/ 100 g]. The protective effect of mastic gum, a resinous exudate of the tree of Pistacia lentiscus Linn Anacardiaceae, [500 mg/Kg], and vitamin E, a well known antioxidant, [100 mg/Kg] were investigated. Different gastric juice components [acidity, mucin and peptic activity] as well as gastric mucosal content of reduced glutathione, malondialdehyde, [as an index of lipid peroxidation] and prostaglandin E2 were estimated. Ethanol/HCl administration produced marked ulcers in the glandular part of rat stomach. Pretreatment with the protective agents significantly reduced the ulcer index and the protection afforded by mastic gum was greater than that of vitamin E. The protective effects of both mastic gum and vitamin E were accompanied by a significant decrease in mucosal content of malondialdehyde and a significant increase in mucosal content of reduced glutathione as compared to ethanol/HCl treated group. However, the anti-ulcer effect produced by mastic gum, only, was associated with a significant increase in mucosal content of prostaglandin E[2]. In 3-hour pylorus-ligated rats, mastic gum produced a significant decrease in free and total acidity while vitamin E caused no significant change in gastric acid secretion. The present data suggest that the anti-ulcer effect of mastic gum may be partly related to its antisecretory as well as antioxidant properties. On the other hand, the protective effect of vitamin E may be mainly related to its antioxidant effect

Effects of cypermethrin on lipid peroxidation and some antioxidant defense mechanisms in rats

Reactive oxygen species [ROS] have been implicated in the toxicity of various insecticides. Pyrethroids, though having the advantage of low mammalian toxicity, have been reported to produce signs of toxicity Most of these are linked to skeletal muscles. The present study tests the ability of single or repeated administration of Cypermethrin, a type II pyrethroids. to induce lipid peroxidation [LPO] in die rat brain, liver and diaphragm tissues. The study included the effect on antioxidant parameters, reduced glutathione [GSH], glutathione peroxidase [GPX], superoxide dismutase [SOD], and the protective effect of vitamin E. Single and repeated [7 days] administration of Cypermethrin [1/10 LD] induced lipid peroxidation in the rat diaphragm, while the brain and liver showed significant lipid peroxidation upon repeated administration only. This was manifested as elevation of the marker malondialdehyde [MDA]. The antioxidant defense parameter. GSH. GPX and SOD were not affected by single dose of Cypennethrin. in the rat brain or liver tissues. while, in the rat diaphragm a significant reduction in glutathione peroxidase was evident. In the rat diaphragm, repeated administration of Cypermethrin increased the level of GSH while decreased GPX activity. No significant effect was shown on the rat brain or iiver tissues. SOD activity was significantly reduced ia he diaphragm while the brain and the liver showed significant increase in the enzyme activity. Prior administration of vitamin E effectively antagonized the changes in LPO and the antioxidant parameters GSH, GPX and SOD induced by Cypennethrin. In conclusion, Cypermethrin induced LPO and an increase in the ROS. This may be linked to the mechanism underlying its insecticidal action as well as its adverse effects. Vitamin E is an effective agent to protect against the lipid peroxydative s power of Cypermethrin

Binding studies of some antidiabetics to serum albumin by difference spectrophotometry

The binding of several antidiabetics to serum albumin was studied by difference spectrophotometry using a spectrophotometric probe 2-[4-hydroxy-benzeneazo] benzoic acid. The calculated constants for binding of the drugs to human serum albumin were 2.38x10[6], 1.78x10[6], and 1.87x10[4] for glyburide, tolbutamide and metformin respectively. While the values of binding to bovine serum albumin were 2.89x10[5], 2.04x10[5], and 2.14x10[4] for the same drugs. Drug-probe displacement studies showed that glyburide gave the greatest probe displacement followed by tolbutamide and metformin using both human and bovine serum albumins. This order of displacement of the anionic probe indicates that both hydrophobic character and ring substituents of the ligand contribute