Avaliação da composição química e do perfil toxicológico e farmacológico dos extratos obtidos do resíduo industrial dos frutos de Passiflora edulis f. flavicarpa O. Deg

Abstract

Hypertension and Diabetes Mellitus are diseases on the rise in the world and can cause several cardiovascular complications. Several drugs have efficacy in the treatment of these diseases, however, many have adverse effects and limitations of efficacy. The peel of the fruit of P. edulis f. flavicarpa O. Degener (yellow passion fruit), considered a waste from the food industry, is rich in bioactive compounds. Thus, due to the need to search for new treatments for hypertension and diabetes, and in order to stimulate the development of herbal medicines with species native to Brazil, the study aimed to evaluate the phytochemical composition, the toxicity profile and the pharmacological potential of P. edulis peel extracts in non-clinical models of hypertension and diabetes. Methodology was divided into the following parts: i: phytochemical study, assessment of antioxidant activity in vitro and acute oral toxicity ii: non-clinical assessment of antihypertensive activity in an ex vivo model of isolated arteries and in chronic model of spontaneously hypertensive rats; iii acute and chronic non-clinical evaluation of antidiabetic activity in models of type 1 diabetes, induced by streptozotocin. Two extracts were produced (aqueous, prepared by decoction-AFA and hydroethanolic -AFM, obtained by maceration) from the peel flour (dry and crushed peel) of P. edulis. Phytochemical analysis was performerd by CCD, UHPLC/UV-DAD and HPLC-ESI-MSn. In both extracts C-glycosylated flavonoids were identified. Among the identified flavonoids, it was possible to quantify the content of vicenin-2, orientin, isoorientin, vitexin and isovitexin by HPLC-QqQ-MS/MS. The polysaccharide pectin was found only in the AFA extract, through high performance steric exclusion chromatography and NMR, its content was 34.3%. According to the results obtained in acute oral toxicity, extracts were classified in category 5 by GSH (Globally Harmonized Classification System for Chemical Substances and Mixtures) with LD50> 2000mg/kg, since they did not show signs of acute toxicity. The in vitro antioxidant assay showed that the extracts have good antioxidant activity observed by TAC, reducing power and DPPH tests. In the evaluation of the antihypertensive effect, it was verified in an ex vivo model of isolated artery that the AFM extract had the best relaxation profile, when compared to AFA. It effect may be due to the opening of the potassium channels. In addition, the AFM extract at doses 200 and 400 mg/kg, orally, showed a significant hypotensive effect after 28 days of treatment and improved vascular function in the mesenteric artery. This was verified by a decrease in vascular hypercontractility and an increase in the vasorelaxant effect in response to sodium nitroprusside and acetylcholine. There was also a decrease in endothelial dysfunction that can be attributed to the increased bioavailability of nitric oxide. Thus, our hypothesis is that all these effects were able to contribute to the reduction of peripheral vascular resistance, causing a significant hypotensive effect. These results are unprecedented for the pericarp of P. edulis. In addition, there was a decrease in plasma MDA levels in the heart and an increase in glutathione, suggesting a decrease in oxidative stress, as well as an increase in plasma of anti-inflammatory cytokines such as IL-10. In the acute in vivo antidiabetic model, it was observed that the extracts at doses of 400 and 600 mg/kg associated with insulin were able to significantly reduce blood glucose, when compared to diabetic rats that received only insulin, being this effect more significant with AFA treatment. In the chronic antidiabetic model, the treatment with the extracts during 60 days caused a significant reduction in glycemia observed at a dose of 400 mg/kg. In addition, extracts decreased MDA in the liver and MPO in the heart and kidney, suggesting that the extracts may act by reducing oxidative stress and inflammation caused in diabetes. Renal fibrosis was also reduced with chronic treatment. Taken together, toxicological and pharmacological studies proved the safe and the potential effect of P.edulis peel fruit extracts in development new phytoterapics.