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

LUCHETTI CG; SOLANO, ME; SANDER V; ELÍA E; MOTTA AB

Miami- USA

Congreso; The Interamerican Society of Hypertension and the Consortium for Southeastern Hipertensión Control Joint Scientific Sessions; 2007

The Interamerican Society of Hypertension and the Consortium for Southeastern Hipertensión Control

Background: 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 decreasesed 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 interleukine-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). Objetive. The purpose of this work was to study the uterine oxidant/antioxidant status, including NO concentrations, and the serum Th1/Th2 cytokines balance. Methods. 8 days- pregnant mice (implantation day 5, treatment days 6 and 7) were divided into the folowing experimental groups: C(control), D (sc 60 mg/kg body weight) and D+M (D sc plus M 250 mg/kg oral by canulla). Oxidative stress: uterine tissues were homogenized and used for determination of ROS production (lipid peroxidation index) and the antioxidant response (Catalase activity). Nitrites concentration (NO index) were quantified by the Griess assay. Serum levels of IL-6 and TNF were quantified by ELISA n=6 group. Results. Oxidative stress: D significantly increased lipid peroxidation (3.1 + 0.1 vs C 2.1 +0.3 Umol malondialdehyde (MDA) /mg protein); M was not able to avoid this increment (D+M 2.8+0.2 Umol MDA/mg protein). Catalase was decreased in D group, but not significantly (0.05 + 0.01 vs C 0.06 + 0.01 pmol/mg protein) and was increased significantly by M  treatment  (D+M  0.10+0.04 pmol/mg protein). The nitrites concentration  was significantly  augmented   by D  (450+27 vs C  296+24 nmol/mg protein)  whereas  M  reverted  this effect  (D+M  346+25 nmol/mg  protein ). Cytokines balance  IL-6  concentration was significantly diminished  in D  group ( 1.7+0.8 vs C 4.8+0.9 pmol/ ml serum) and this diminution was reverted with M (D+M 5.7+0.3 pmol/ml serum). TNF was significantly augmented in D (118+14 vs C 80+15 pg/ml serum) whereas M was able to prevent this effect (D+M 74+15 pg/ml serum). Conclusions. M prevents ER caused by D- hyperandrogenization protecting  uterine tissues against oxidation (by increasing catalase activity and diminishing nitrites concentration) and regulating Th1/Th2 cytokines balance (restoring IL-6 and TNF to control levels).