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.
Ahmad Aqsa, Saleem Ammara
Abstract
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.
Key Findings
- Harmine treatment normalized metabolic and lipid profiles and restored hormonal balance in letrozole-induced PCOS rat model.
- Harmine reduced serum levels of inflammatory cytokines TNF-α and IL-6 and downregulated their mRNA expression along with Keap-1, while upregulating Nrf2 expression.
- Harmine improved ovarian histology and steroidogenic gene expression in a dose-dependent manner, indicating enhanced ovarian function.
Clinical Significance
Harmine shows therapeutic potential for managing PCOS by modulating oxidative stress, inflammation, and ovarian steroidogenesis, suggesting it could be a safe and effective treatment option for improving reproductive and metabolic outcomes in PCOS patients.
Citation
Ahmad Aqsa, Saleem Ammara. 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. Naunyn-Schmiedeberg's archives of pharmacology. 2026-Jun-06.