Therapeutic potential of harmine in polycystic ovarian syndrome: regulation of TNF-α/IL-6-mediated inflammation, Nrf2/keap-1 signaling, and ovarian steroidogenesis in Sprague-Dawley rats.

Polycystic ovarian syndrome (PCOS) is an intricate endocrine and metabolic disorder affecting reproductive-age women. This research focused on assessing the therapeutic potential of harmine in letrozole-induced PCOS rat model. PCOS was induced in all the groups except normal control by oral administration of letrozole (1 mg/kg) for consecutive 28 days. After confirmation of PCOS, normal and disease controls were treated with vehicle, clomiphene citrate (5.25 mg/kg) was administered as a standard drug, and harmine as treatment compound at 2.5, 5.0, and 10 mg/kg orally for 28 days daily. Letrozole administration in diseased rats displayed disrupted estrous cycle irregularity, insulin resistance, cystic ovarian morphology, and hyperandrogenism along with upregulation of metabolic and lipid profile and alteration in hormonal and hematological parameters. Treatment with harmine (2.5-10 mg/kg) was remarkably (p < 0.05) normalize the metabolic and lipid profile, restored the hormonal imbalance, and improved ovarian histology. Treatment with harmine (2.5-10 mg/kg) notably reduced the serum level TNF-α, and IL-6 in contrast to disease control. Harmine-treated rats exhibited the down regulation of mRNA expression of TNF-α, IL-6, PGR, and Keap-1 while upregulated FSHR, CYP19A1, and Nfr-2 as equated to disease control. However, harmine demonstrated dose-dependent improvement in mRNA expression that linked with ovarian function. These findings concluded that harmine exhibited promising therapeutic potential for PCOS by modulating metabolic, endocrine, anti-oxidant, anti-inflammatory, and steroidogenic markers. Besides, harmine was safe in acute usage and LD50 > 2000 mg/kg.