Myricetin ameliorates letrozole-induced PCOS in female rats-a mechanistic approach through in silico, in vitro, and in vivo study via P13/AKT and NF-κB pathway crosstalk.

Abstract

Polycystic ovarian syndrome (PCOS) is one of the leading causes of abnormalities in young female patients. Myricetin is flavonoid which has multiple pharmacological effects like anti-inflammatory, antidiabetic, and anticancer. This study determined the effect of myricetin in the treatment of PCOS. For in silico studies, network pharmacology and molecular docking and simulation were done through multiple software tools. In vitro evaluation was done through antioxidant assays (DPPH and ABTS). Female Sprague Dawley rats were used in six groups. Letrozole (1 mg/kg) in 0.5% CMC was used to induce PCOS for 21 days, while CMC was the only treatment given to the normal control. Metformin (20 mg/kg) or myricetin (75, 150, and 300 mg/kg) was administered for 15 days. On day 37, ovarian tissues were homogenized for antioxidant tests and RT-qPCR gene expression analysis, reproductive organs were gathered for histology, and blood was processed for ELISA and LFTs. Network pharmacology shows significant effects of myricetin within the body; however, molecular docking and simulation studies show that Protein kinase B (AKT) has a greater binding capacity with myricetin. It also shows maximum antioxidant activity through antioxidant assays. Myricetin's safety was validated by biochemical, oxidative stress, and histopathological analyses. It enhanced follicular structures and significantly reduced body weight and ovarian cysts. By lowering testosterone (0.265 ± 0.021 mIU/mL vs. 0.735 ± 0.14), LH (0.518 ± 0.009 vs. 2.005 ± 0.027), insulin (11.56 ± 0.40 vs. 29.21 ± 0.59), and corticosterone (51.8 ± 0.79 vs. 115.5 ± 2.9), while increasing FSH (0.87 ± 0.30 mIU/mL vs. 0.36 ± 0.04), myricetin restored antioxidant status. Gene expression analysis shows higher level of PCOS-related genes. Given that these effects were similar to those of metformin, myricetin appears to be a promising treatment option for PCOS.