Oxyberberine revokes letrozole-induced polycystic ovarian syndrome and depression-like behavior in female Sprague-Dawley rats

Polycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder in reproductive-age women, which also negatively perturbs person's psychiatric health. Herein, we investigated the effect of oxyberberine on PCOS- and depression-like phenotypes in female Sprague-Dawley rats. To generate PCOS- and depression-like phenotypes, rats were injected with letrozole (1 mg/kg/day for 21 days) and exposed to 14 days of chronic-unpredictable mild stress (CUMS). We synthesized oxyberberine from its natural parent phytoconstituent i.e., berberine. Rats underwent letrozole + CUMS exposure displayed an increased number of neutrophils in a vaginal smear test indicating a PCOS-like phenotype (i.e., disrupted estrus cycle). Moreover, these rats also showed anhedonia-, depression-, and anxiety-like behaviors in the sucrose-preference test, forced-swimming test, and elevated plus-maze test. Peroral administration of oxyberberine for 21 days, at 50 and 100 mg/kg doses, reversed letrozole + CUMS generated perturbations in rats. The total exploratory behavior in the open field test remained unaffected across the treatment groups. Oxyberberine treatment also restored the organ-weight index of the ovary and uterus and follicular development of the ovary. Systemic and uterine levels of oxyberberine were found to be 0.17–0.80 ng/mL and 1.03–3.62 ng/mL, respectively measured using a liquid chromatography-mass spectrometry assay. Oxyberberine also positively modulated the levels of catalase and malondialdehyde in intestine and spleen, and testosterone and luteinizing hormones in the systematic circulation and CYP17A1, CYP19A1, and SHBG expression in the ovary. These results suggest that oxyberberine improves PCOS- and depression-like phenotypes in rats by modulating testosterone hormone, CYP17A1, CYP19A1, and SHBG enzyme expression in the ovary.