Efeito dos triterpenos ácido oleanólico, ácido ursólico e alfa, beta-amirina no distúrbio metabólico induzido por olanzapina em camundongos e em células 3t3-l1

Abstract

Olanzapine (OLZ) is an atypical antipsychotic drug used in the treatment of schizophrenia that has adverse metabolic effects such as: weight gain, hyperglycemia and insulin resistance. In the present study, the protective effect of pentacyclic triterpenes oleanolic acid (AO), ursolic acid (AU) and alpha, beta-amirine (AMI) on metabolic disorders caused by the administration of OLZ in experimental models in mice C57BL6 and in 3T3-L1 cells was evaluated. The mice were divided into 5 groups: fed with standard diet (DP), fed with the diet associated with OLZ (DO), fed with DO and treated with AO (20 mg/kg), AU (10 mg/kg) and AMI (20 mg/kg), in drinking water during the last 6 of the 9 weeks of treatment. The open field behavioral test and the intraperitoneal glucose tolerance test (TTGI) were performed one week before the end of the treatments. After the animals were euthanized, serum and tissue analysis were performed with the collected materials. The number of crossings in the open field test increased with the AO and AMI treatments, when compared to the DO group, obtaining results close to the DP group. AU treatment, on the other hand, did not generate behavioral changes in comparison to the DO group. The animals in the AO and AMI groups showed a significant decrease in body weight, in BMI, as well as in the weight of the liver regarding the DO group. In addition, treatment with AO increased the weight of subscapular fat in contrast to the DO group. The treatments with the AO, AU and AMI triterpenes reversed the increase in the plasma glucose level caused by OLZ in the DO group. However, only treatment with AO managed to regulate plasma insulin levels, decreased the HOMA-IR index and the area under the curve in the intraperitoneal glucose tolerance test, in addition to increasing hepatic glycogen, thus reversing insulin and glucose resistance caused by treatment with OLZ. Due to the better metabolic results in the animals, the histology and the Western blot tests followed only with the AO triterpene. There was not difference in the histology between the groups in both hepatic or adipose tissue. The DO group had an increase in the expression of p-IRS (ser307) and a significant decrease in the expression of p-AKT in the liver, with consequent decrease in mGLUT expression in muscle when compared to DP, changes that were reversed by the treatment with AO. In a cell model with 3T3-L1 pre-adipocytes, the non-toxic concentrations used were AO = 6.25; 12.5; 25 μM; AU = 3.125; 6.25; 12.5 μM; and AMI = 12.5; 25; 50 μM. The cells underwent adipogenesis with the treatment with OLZ 10 μM in a similar way to the positive control, rosiglitazone 2 μM. There was an increase in intracellular lipid content, which was reversed by practically all tested treatments. OLZ also increased triglycerides and intracellular total cholesterol. All the tested doses of AO managed to reduce these parameters in the cells, a result not seen in the treatments with AU and AMI. For the best biochemical results in the cells, Western blot tests followed only with the AO triterpene. Regarding protein expression, it was noted that treatment with OLZ increased the expression of SREBP-1 and FAS and decreased the expression of pAMPK / AMPK. The 25 μM dose of AO was able to regulate all expressions altered by the treatment with OLZ. Thus, these results indicate that, among the tested triterpenes, AO is a potential adjuvant to prevent metabolic dysfunction, through the PI3K / AKT pathway, and weight gain, through the AMPK / SREBP-1 pathway, caused by the administration of OLZ.