The treatment with metformin in oxidative stress and cytokines balance during hyperandrogenized early pregnancy

LUCHETTI, C. G.; SOLANO, M. E.; SANDER, V. A.; ELIA, E.; MOTTA, AB

Miami, Florida, USA

Congreso; Inter American Society of Hipertensión and Consortium for Southeastern Hipertensión control Joint Meeting,; 2007

Inter American Society of Hipertensión and Consortium for Southeastern Hipertensión control Joint Meeting,

The insulin-sensitizing drug Metformin(M) is used in the treatment of polycystic ovary syndrome(PCOS), but its mechanism of action is still unknown. This biguanide was reported to be scavenger of reactive oxygen species(ROS). Moreover, it has been observed a decreased antioxidant capacity in women with PCOS that could contribute to the increased risk of cardiovascular diseases as atherosclerosis or hypertension. Nitric oxide(NO) plays an important role in pregnancy and vascular function, and could be a precursor of reactive nitric oxide species. On the other hand, the Th2 cytokine interleukin-6(IL-6) and the Th1 cytokine tumor necrosis factor(TNF) have been reported as modulators of arterial pressure and pregnancy. In previous studies we have observed that M prevented embryo resorption(ER) diminishing the ovarian oxidative stress produced by dehydroepiandrosterone(D).Objective.The purpose of this work was to study: the uterine oxidant/antioxidant status, including NO concentrations, and the serum Th1/Th2 cytokines balance.Methods.8days-pregnant mice(implantation day 5, treatment days 6and7) were divided into the following experimental groups: C(control), D(sc 60mg/kg body weight) and D+M(D sc plus M 250mg/kg oral by canulla). Oxidative stress: uterine tissues were homogeinized and used for determination of ROS production (lipid peroxidation index) and the antioxidant response (catalase activity). Nitrites concentrations(NO index) were quantified by the Griess assay. Serum levels of IL6 and TNF were quantified by ELISA. n=6/group.Results.Oxidative stress: D significantly increased lipid peroxidation(3,1+0,1vsC 2,1+0,3 Umol malondialdehyde(MDA)/mg protein); M was not able to avoid this increment(D+M2,8+0,2 Umol MDA/mg protein). Catalase was decreased in D group, but not significantly(0,05+0,01vsC 0,06+0,01 pmol/ mg protein) and was increased significantly by M treatment(D+M0,10+0,04 pmol/ mg protein). The nitrites concentration was significantly augmented by D(450±27vsC 296±24nmol/mg protein) whereas M reverted this effect(D+M346±25nmol/mg protein). Cytokines balance: IL-6 concentration was significantly diminished in D group(1,7±0,8vsC 4,8±0,9pmol/ml serum) and this diminution was reverted with M(D+M 5,7±0,3pmol/ml serum). TNF was significantly augmented in D(118+14 vs C80+15pg/ml serum) whereas M was able to prevent this effect(D+M74+15pg/ml serum).Conclusions.M prevents ER caused by D-hyperandrogenyzation, protecting uterine tissue against oxidation(by increasing catalase activity and diminishing nitrites concentration) and regulating the Th1/Th2 cytokines balance(restoring IL-6 and TNF to control levels).