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Febuxostat attenuates testosterone-induced benign prostatic hyperplasia in rats via inhibiting JAK/STAT axis
Amira M Abo-Youssef1, Hassan Afify2, Amany A Azouz1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
Aim:
To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis.
Main Methods:
Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues.
Key Findings:
Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1β (IL-1 β), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression.
Significance:
Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.
Insights
Febuxostat treatment reduced prostate size and improved tissue structure in rats with benign prostatic hyperplasia (BPH). It works by inhibiting the xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) pathway.
Area of Science:
- Pharmacology
- Urology
- Biochemistry
Background:
- Benign prostatic hyperplasia (BPH) is a common condition in aging men.
- Testosterone administration in rats is a model for inducing BPH.
- The xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activation of transcription (STAT) axis is implicated in BPH pathogenesis.
Purpose of the Study:
- To investigate the modulatory effect of febuxostat on testosterone-induced BPH in rats.
- To assess the role of the XO/JAK/STAT axis in febuxostat's effect on BPH.
Main Methods:
- Male Wistar rats were treated with testosterone with or without febuxostat.
- Histopathology, prostate weight/index, cyclin D1 expression, and Bax/Bcl-2 ratio were assessed.
- XO activity, uric acid, oxidative stress markers (MDA, SOD, GSH), inflammatory markers (IL-6, IL-1β, TNF-α, NF-κB), JAK-1, and STAT-3 phosphorylation were evaluated.
Main Results:
- Febuxostat reduced prostate weight, index, and ameliorated histopathological changes in BPH rats.
- Febuxostat decreased cyclin D1 expression, enhanced Bax/Bcl-2 ratio, and suppressed XO activity and uric acid levels.
- Febuxostat regulated oxidative stress and inflammatory markers and inhibited JAK-1 and STAT-3 phosphorylation.
Conclusions:
- Febuxostat ameliorates testosterone-induced BPH in rats by suppressing the XO/JAK/STAT axis.
- These findings suggest a potential repurposing of XO inhibitors for BPH treatment.
Related Concept Videos
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01:26Testosterone: Functions and Regulation