Metabolic and Endocrine Modulation by a Novel 1,2,3,6-Tetrahydropyridine- Substituted 7-Azaindole Derivative in a Polycystic Ovarian Syndrome Rat Model
Maryam Mehmood, Sadaf Naeem, Sajda Ashraf, Anosh Tahir, Shazia haider, Faheema Siddiqui, Zafar Saied Saify, Saira Saeed KhanIntroduction/Objective:
Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disorder whose reproductive, metabolic, and inflammatory features are not adequately addressed by existing single-mechanism therapies. A1, a novel 7-azaindole derivative (1-methyl -4- {1H-pyrrol [2,3-b] pyridine-3-yl-1, 2, 3, 6-tetrahydropyridine), was selected based on its structural resemblance to melatonin, which has been reported to possess antidiabetic properties. This study evaluated the reproductive, hormonal, and glycemic effects of A1 for the treatment of PCOS in a rat model.
Methods:
Sixty virgin female Albino Wistar rats (n=15/group across four groups: control, negative control/PCOS, standard [metformin], and A1-treated) were induced with PCOS by administering oral letrozole and were treated with A1 for 30 days. A subset of animals (n=3/group) received extended treatment for 60 days to assess subchronic toxicity. Evaluations included ovarian histopathology, hormonal assays, glycemic parameters, lipid profiling, cytotoxicity assays, molecular docking, and gene expression analysis.
Results:
A1 treatment eliminated ovarian cysts, restored estrous cyclicity (89.36% by day 21-28, versus 0% in the PCOS group), improved lipid profiles, and restored hormonal profiles (reducing testosterone, LH, and estradiol while increasing FSH and SHBG toward control values; p<0.01). A1 exhibited alpha-glucosidase inhibitory activity (63.45% inhibition; IC50 88±5.7 μM) and antioxidant activity (83.25% DPPH scavenging at 100 μg/ml). However, extended administration was associated with histological changes in the liver and kidney suggestive of potential hepatic and renal stress, which warrants confirmation with biochemical toxicity markers.
Discussion:
A1's therapeutic effects likely reflect combined hormonal restoration and glucose-lowering activity consistent with its structural resemblance to melatonin, while the predicted FSHR interaction identified by molecular docking remains a computational hypothesis that has not yet been functionally validated. The hepatic and renal histological changes observed after extended dosing, together with the absence of biochemical toxicity markers and in vivo pharmacokinetic data, indicate that further structural optimization and toxicological characterization are needed before A1 can be considered for clinical development.
Conclusion:
A1 significantly restored endocrine and hormonal markers, glucose, insulin, and dyslipidemia while enhancing FSHR gene expression; molecular docking predicted binding within the FSHR allosteric pocket, a finding not yet functionally validated. These results indicate that A1, a novel 7-azaindole derivative, may regulate reproductive and metabolic dysfunctions in PCOS through endocrine modulation and receptor-- mediated mechanisms, demonstrating significant therapeutic potential for PCOS and ameliorating key metabolic and endocrine disturbances. While promising, its toxicity profile warrants further structural optimization for clinical development.