Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus.

AIMS/HYPOTHESIS: We investigated the effect of SB 203580, a pharmacological inhibitor of p38 mitogen-activated protein kinase (MAPK), on cardiac inflammation, cardiac fibrosis, and left ventricular function using an animal model of diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by streptozotocin (50 mg/kg i.p. for 5 days) in 20 C57/BL6J mice. Diabetic mice were treated daily with the p38 MAPK inhibitor SB 203580 (1 mg/kg daily, n=10) or with placebo (n=10) and were compared to non-diabetic controls. Left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. The parameters for systolic function were the end systolic pressure-volume relationship (ESPVR) and the left ventricular end systolic pressure. The parameters for diastolic function were the left ventricular end diastolic pressure and the end diastolic pressure-volume relationship (EDPVR). Cardiac tissue was analysed by ELISA for the protein content of the cytokines TNF-alpha, IL6, IL1-beta, and TGF-beta1. Phosphorylation of MAPK p38 was analysed by western blot, and the total cardiac collagen content was analysed by Sirius red staining. RESULTS: Left ventricular dysfunction was documented by impaired ESPVR and EDPVR. Cardiac cytokine levels and cardiac fibrosis were increased in diabetic animals compared to controls. Treatment with the p38 inhibitor normalised cardiac cytokine levels and improved systolic function, but did not change cardiac fibrosis and diastolic dysfunction compared to placebo. CONCLUSIONS/INTERPRETATION: Pharmacological inhibition of p38 MAPK prevents cardiac inflammation and attenuates left ventricular dysfunction in diabetic cardiomyopathy.

[Effect of various combinations of DL-alpha-tocopherol and acetylsalicylic acid on adjuvant arthritis in the rat]. / Einfluss verschiedener Kombinationen von DL-alpha-tocopherol und Acetylsalicylsäure auf die Adjuvansarthritis der Ratte.

The influence of per os application of different combinations of DL-alpha-tocopherol (TOC) and acetylsalicylic acid (ASS) on adjuvant-induced arthritis was tested in male Wistar rats (body weight 227 +/- 18 g; 8 groups, n = 8). One group (control) was without adjuvans arthritis and received no treatment, another group was also not treated in spite of adjuvans arthritis. Further, six groups of adjuvans arthritis were treated with the following combinations: ASS/TOC (mg/kg BW/d each) 250/-, 250/250, 167/250, 83/250, 167/167 and 167/83. During the course of the experiment (21 d), body weights, food intake, and the swelling of injected and noninjected paws, and (at the end of the test period) relative weight of spleen and the albumin-globulin-ratio in plasma were recorded. With the ASS/TOC combination of 250 mg/kg BW each, the highest antiinflammatory effect could be reached, as compared with all treated groups. The reduction of acetylsalicylic acid does by one-third to 167 mg/kg BW in combination with 250 mg DL-alpha-tocopherol/kg BW seem to have the same antiphlogistic effect as acetylsalicylic acid alone at 250 mg/kg BW. This positive effect could be confirmed by the partially normalized relative spleen weight and albumin-globulin-ratio. The results allow the conclusion: --main antiphologistic effect of the combination is due to acetylsalicylic acid; --when combined with 250 mg DL-alpha-tocopherol/kg BW acetylsalicylic acid dosage can be reduced by one-third to 167 mg/kg BW and still have the same effect as ASS alone (250 mg/kg BW); --further reductions of ASS and/or DL-alpha-tocopherol dosage minimize the antiinflammatory effect.

[Effect of vitamin E on experimental inflammation in rats]. / Untersuchungen über den Einfluss von Vitamin E auf eine experimentelle Entzündung an Ratten.

Besides other mediators like prostaglandins, kinins and histamine, oxygen radicals potentiate inflammations. Vitamin E as natural antioxidant could scavenge radicals produced during an inflammation and therefore reduce the inflammatory response. In experiments with male Wistar rats maintained on a diet deficient in or supplemented with vitamin E for 6 weeks the influence of the administration of DL-alpha-tocopherol on the inflammation of the right hind paw was tested. The irritation produced by injection of Freund's complete adjuvants was observed for 21 days. Measuring the thickness of the paw and the activity of acid phosphatase in the paw tissue there was no difference in the intensity of inflammation among the control and the vitamin-E-deficient diet groups. The supplementation with a pharmacological dose of tocopherol (324 mg DL-alpha-tocopherol/100 g food) had no effect on the inflammation of animals with different vitamin E supplements. Differences in the antioxidant status (contents of tocopherol and malondialdehyde in several organs, activity of creatine kinase in plasma) among the groups were mainly linked to the various tocopherol supplies. The irritation increased the lipid peroxidation in liver mitochondria and the activity of creatine kinase in the plasma. The data show no influence of vitamin E on this kind of inflammation.