Fenofibrate mitigates testosterone induced benign prostatic hyperplasia via regulation of Akt/FOXO3a pathway and modulation of apoptosis and proliferation in rats

• Published in: Archives of biochemistry and biophysics 2022-07, Vol.723, p.109237-109237, Article 109237
• Main Authors: Kortam, Mona A., Alawady, Asmaa S., Hamid Sadik, Nermin Abdel, Fathy, Nevine
• Format: Article
• Language: English
• Subjects: Akt; Animals; Apoptosis; BPH; Cell Proliferation; Fenofibrate; Fenofibrate - adverse effects; FOXO3a; Humans; Male; Prostatic Hyperplasia - chemically induced; Prostatic Hyperplasia - drug therapy; Prostatic Hyperplasia - metabolism; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Testosterone - metabolism
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2022.109237

Benign prostatic hyperplasia (BPH) is one of the most age-related health problems that commonly affect men. Regrettably, many individuals may not respond to current medical therapies or develop resistance to them. Accordingly, this study aimed to uncover how potentially fenofibrate, a lipid lowering agent, can ameliorate the induced BPH in rats. Forty rats were categorized randomly into four groups; the control group was given the vehicle (olive oil); the BPH model received testosterone propionate (20 mg/kg daily; s.c.) for 4 weeks; BPH-induced group received finasteride (10 mg/kg daily; p.o.) and BPH-induced group received fenofibrate (80 mg/kg daily; p.o.). After testosterone administration, both weight and relative weight of the prostate increased. Additionally, testosterone upregulated androgen receptor (AR), 5α-reductase gene expression and increased prostate proliferation. Histopathological examination confirmed that testosterone disrupted the histo-architecture of the prostate and caused marked hyperplasia of glands and stroma. On the other hand, fenofibrate administration reverted most hyperplastic changes of testosterone, it significantly reduced weight, relative weight of the prostate and dihydrotestosterone (DHT) level compared to BPH group. Also fenofibrate significantly decreased AR and 5α-reductase gene expression. Fenofibrate significantly suppressed ps473 Akt expression causing FOXO3a nuclear inclusion, which triggered induction of apoptosis. As well, Bax/Bcl2 ratio and caspase 3 content were significantly enhanced. Fenofibrate significantly diminished cyclin D1 immunoexpression and restored normal histo-architecture. In conclusion, this study emphasizes the preventive effect of fenofibrate in BPH rat model. This can be accredited, at least partly, to inhibiting AR and 5α-reductase expressions, the anti-proliferative, and pro-apoptotic activity of fenofibrate via modulation of Akt/FOXO3a pathway. [Display omitted] •Fenofibrate alleviated testosterone induced BPH in rats.•Fenofibrate decreased prostate weight and normalized serum DHT level.•Fenofibrate reduced AR and 5α- reductase genes expression.•Fenofibrate induced apoptosis via nuclear translocation of FOXO3a by modulating Akt phosphorylation.•Fenofibrate increased Bax/Bcl2 ratio and caspase3 activity.