Canagliflozin alleviates experimentally induced benign prostate hyperplasia in a rat model: exploring potential mechanisms involving mir-128b/EGFR/EGF and JAK2/STAT3 signaling pathways through in silico and in vivo investigations

Benign prostatic hyperplasia (BPH) poses a significant health concern amongst elderly males. Canagliflozin (Cana), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has a powerful anti-inflammatory influence. Nevertheless, its role in treating BPH has not been clarified. Therefore, the study aimed to investigate the potential ameliorative effect of Cana on experimentally induced BPH in rats and explore the underlying mechanisms compared to the standard finasteride (Fin). The study employed histological analysis, biochemical assays using ELISA, and western blotting. Animals were categorized into four groups: Control (2.5 ml/kg CMC, orally + 3 ml/kg olive oil, subcutaneous), BPH (3 mg/kg testosterone, subcutaneous + CMC orally), Fin-treated BPH (5 mg/kg, orally), and Cana-treated BPH (5 mg/kg, orally), for 28 days. The BPH group showed obvious BPH manifestations including an increase in prostate weight (PW), prostate index (PI), dihydrotestosterone (DHT) level, and histological aberrations compared to control. Fin and Cana therapy had a comparable impact. Cana treatment significantly reduced PW and PI, besides it improved prostatic biochemical, and histopathological features compared to BPH, consistent with in silico study findings. Cana was associated with downregulation of the androgen axis, increased miR-128b expression, with a lowered expression of epidermal growth factor (EGF) and its receptor. Phosphorylation of STAT3 and its downstream proliferative markers were significantly reduced suggesting apoptotic activity. Cana markedly rescued the BPH-induced upregulation of IL-1β, and iNOS levels. Altogether, the current study demonstrates that Cana could impede BPH progression, possibly by modulating miR-128b/EGFR/EGF and JAK2/STAT3 pathways and downregulating AR, cyclin D1, and PCNA immunoreactivity.