Simvastatin ameliorates testosterone-induced prostatic hyperplasia in rats via modulating IGF-1/PI3K/AKT/FOXO signaling

• Published in: European journal of pharmacology 2023-07, Vol.950, p.175762-175762, Article 175762
• Main Authors: El-Shafei, Nyera H., Zaafan, Mai A., Kandil, Esraa A., Sayed, Rabab H.
• Format: Article
• Language: English
• Subjects: AKT; Animals; Antioxidants - adverse effects; Benign prostatic hyperplasia; FOXO; IGF-1; Insulin-Like Growth Factor I; Male; Olive Oil - pharmacology; Olive Oil - therapeutic use; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Prostatic Hyperplasia - chemically induced; Prostatic Hyperplasia - drug therapy; Prostatic Hyperplasia - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Testosterone; Water
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175762

Benign prostatic hyperplasia (BPH) is characterized by non-malignant enlargement of prostate cells causing many lower urinary tract symptoms. BPH pathogenesis includes androgens receptors signaling pathways, oxidative stress, apoptosis, and possibly changes in IGF-1/PI3K/AKT/FOXO pathway. Altogether, modulating IGF-1/PI3K/AKT/FOXO signaling along with regulating oxidative stress and apoptosis might preserve prostatic cells from increased proliferation. Beyond statins' common uses, they also have anti-inflammatory, antioxidant, and anti-tumor effects. This study aims to determine simvastatin's beneficial effect on testosterone-induced BPH. Rats were randomly allocated into four groups, 9 rats each. The control group received olive oil subcutaneously and distilled water orally for 30 consecutive days. The second group received simvastatin (20 mg/kg, p.o.) dissolved in distilled water. The BPH-induced group received testosterone enanthate (3 mg/kg, s.c.) dissolved in olive oil, and the BPH-induced treated group received both simvastatin and testosterone. Testosterone significantly increased prostate index and severity of histopathological alterations in prostate tissues as well as 5-alpha reductase enzyme level in contrast to simvastatin treatment that reversed the testosterone-induced alterations in these parameters. Likewise, testosterone up-regulated IGF-1/PI3K/AKT signaling pathway and down-regulated FOXO transcription factor. It also decreased apoptotic markers level in prostatic tissue BAX, caspase-3, and caspase-9, while it elevated Bcl-2 level. In addition, it alleviated reduced GSH and GPX5 levels and SOD activity. Simvastatin treatment significantly opposed testosterone's effect on all aforementioned parameters. In conclusion, this study demonstrates that simvastatin is a possible treatment for BPH which may be attributed to its effect on IGF-1/PI3K/AKT/FOXO signaling pathway as well as anti-oxidant and apoptotic effects. •Simvastatin ameliorates testosterone-induced prostatic hyperplasia.•Simvastatin modulates IGF-1/PI3K/AKT/FOXO pathway in prostatic tissue.•Simvastatin shows an apoptotic and an anti-oxidant activity in prostatic tissues.