Isolation and Pharmacological Evaluation of Quercetin in Treatment of Polycystic Ovarian Syndrome: Role of Phosphatidylinositide 3-Kinase

Abstract

Aim and Objective: Polycystic Ovary Syndrome (PCOS) is well recognized as being major endocrinopathy in women. The current therapeutic options in clinical practice for PCOS involve insulin sensitizers and clomiphene citrate. However, randomized clinical trials have shown the potential safety problems associated with long term use of these therapies and not targeting all consequences of disease. Therefore, there is an urge of development of new treatment strategy for PCOS. Quercetin is used as antioxidant and hypoglycemic agent since long and its use has been extended to cancer in clinical practice in the modern times. Therefore, the present study aims at evaluating the role of quercetin and its mechanism of action in testosterone propionate induced animal model of PCOS. Materials and methods: Docking study of Quercetin with Phosphatidylinositide 3-Kinase was carried out with SYBYL and GOLD software. Isolation of quercetin from Neem (Azadirachta indica) leaves was performed. In In-vivo pharmacological evaluation of Quercetin, forty threeweeks- old female Sprague Dawley rats were randomly assigned in four groups. Group 1 (n=10): Normal Control, Group 2 (n=10): Diseased Control, Group 3 (n=10): Diseased + Standard treatment group, Group 4 (n=10): Diseased + Test treatment group. The rats were given testosterone propionate (1 mg/100 gm body weight) subcutaneously for five weeks for inducing PCOS in respective group. After 5th week, the rats were treated with metformin or Quercetin in their respective groups for four weeks. At the end of 5th and 9th week of experiment, after blood collection, Body weight, weight of ovary and uterus and serum levels of testosterone, LH, insulin, HDL, triglyceride and cholesterol were measured. The ovary was subjected to histopathology as well as used for evaluating gene expression by Polymerase Chain Reaction. From the slide prepared of the section, follicular count and number of corpus luteum were counted. Results: Isolation of quercetin from Azadirachta indica showed yield of 35.2 mg quercetin/ 100 gm of Neem powder. Furthermore, comparison of the isolated quercetin with the standard quercetin solutions confirmed the isolated extract to be of Quercetin based on the Rf value. Docking score of Quercetin with PI3K was found to be higher as compared to the other reported PI3K inhibitors. In present study, body weight and uterine and ovary weight were found to be decreased by the treatments with quercetin and metformin. It was observed that serum insulin, testosterone, LH, triglyceride, cholesterol, LDL, VLDL were significantly (P<0.01) higher in the diseases group as compared to normal control group. Treatment with quercetin produced statistically significant (P<0.01) decrease in all these parameters. While, the serum level of HDL decreased significantly (P<0.01) in the diseased state and by the treatment with quercetin, HDL levels were found to be improved. Histological examination of ovary and uterus confirmed the disease occurrence and remission state in the diseased and treated groups, respectively. The biochemical parameters improved with quercetin were comparable to metformin treatment. The CYP17A1 gene expression was observed to be higher in the diseased group and treatment showed decrease in the expression of CYP17A1 gene. Conclusion: The present findings suggest that quercetin exerts curative action on the testosterone propionate induced PCOS. The efficacy of quercetin is comparable to that of metformin. Thus, we can conclude that quercetin has ameliorating effect against PCOS by virtue of inhibition of PI3K which attributes to decrease in expression of CYP17A1 gene is having key role in steroidogenic activity.