Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms

Li, Jing; Tian, Yanxin; Guo, Shimeng; Gu, Haifeng; Yuan, Qianting; Xie, Xin

doi:10.1371/journal.pone.0191469

Cited by 38 publications

(32 citation statements)

References 35 publications

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“…Since Kato et al (1965) has reported pathologic growth of prostate tissue in TP-treated rats, this experimental model has been widely used by researchers for BPH research ( Maggi et al, 1989 ; Shin et al, 2012 ; Li et al, 2018 ). Based on this TP-induced BPH rat model, we attempted to elucidate the effect of BBR.…”

Section: Discussionmentioning

confidence: 99%

Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro

et al. 2018

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Benign prostate hyperplasia (BPH) is a common disease in elderly men, characterized by proliferated prostate and urinary tract symptoms. The hormonal cascade starting by the action of 5-alpha-reductase (5AR) is known to be one of the pathways responsible for the pathogenesis of BPH. Present investigation evaluated the capacity of berberine (BBR), a nature-derived compound abundant in Coptis japonica, in testosterone-induced BPH rats. Experimental BPH was induced by inguinal injection with testosterone propionate (TP) for 4 weeks. BBR or finasteride, a 5AR inhibitor as positive control, was treated for 4 weeks during BPH. BPH induced by TP evoked weight gaining and histological changes of prostate and BBR treatment improved all the detrimental effects not only weight reduction and histological changes but also suppression of prostate-specific antigen (PSA), which is elevated during BPH. Additionally, BBR suppressed TP-associated increase of 5AR, androgen receptor (AR) and steroid coactivator-1 (SRC-1), the key factors in the pathogenesis of BPH. To evaluate the underlying molecular mechanisms responsible for beneficial effects of BBR, we investigated whether these effects were associated with the mitogen-activated protein kinase pathway. BPH induced by TP showed increased phosphorylation of extracellular signal-regulated kinase (ERK), whereas this was suppressed by BBR treatment. On the other hand, c-jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase was not changed in BPH rats. In in vitro study using RWPE-1 cells, a human prostate epithelial cell line. TP increased cell proliferation and BPH-related key factors such as PSA, AR, and 5AR in RWPE-1 cells, and those factors were significantly decreased in the presence of BBR. Furthermore, these proliferative effects in RWPE-1cells were attenuated by treatment with U0126, an ERK inhibitor, confirming BBR can relieve overgrowth of prostate via ERK-dependent signaling. The cotreatment of U0126 and BBR did not affect the change of 5AR nor proliferation compared with U0126 alone, suggesting that the effect of BBR was dependent on the action of ERK. In conclusion, this study shows that BBR can be used as a therapeutic agent for BPH by controlling hyperplasia of prostate through suppression of ERK mechanism.

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Section: Discussionmentioning

confidence: 99%

Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro

et al. 2018

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“…These results further support the notion that supra-physiologic testosterone increases voiding frequency and are consistent with increased voiding frequency in rats and dogs supplemented with testosterone. 40…”

Section: Resultsmentioning

confidence: 99%

Factors Driving Unique Urination Phenotypes of Male and Female 9-week-old C57BL/6J Mice

Ruetten

Wegner

Zhang

et al. 2019

Preprint

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Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of Lower Urinary Tract Symptoms (LUTS). Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomical, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations. We performed void spot assay and cystometry to establish a multi-parameter “baseline” of voiding function in intact male and female 9-week-old (adult) C57BL/6J mice. We then compared voiding function in intact male mice to that of castrate males, males (and females) treated with the steroid five alpha reductase inhibitor finasteride, or males harboring alleles (Pbsn4cre/+;R26RDta/+) that significantly reduce prostate lobe mass by depleting prostatic luminal epithelial cells. We evaluated aging-related changes in male urinary voiding. We also treated intact male, castrate male, and female mice with exogenous testosterone to determine the influence of androgen on voiding function. The three methods used to reduce prostate mass (castration, finasteride, Pbsn4cre/+; R26RDta/+) changed voiding function from baseline but in a nonuniform manner. Castration feminized some aspects of male urinary physiology (making them more like intact female) while exogenous testosterone masculinized some aspects of female urinary physiology (making them more like intact male). Our results provide evidence that circulating testosterone is responsible in part for baseline sex differences in C57BL/6J mouse voiding function while prostate lobe mass in young, healthy adult mice has a lesser influence.

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“…The testosterone-induced rat with BPH was used to explore the study about the development of obstruction in micturition and evaluation of drugs targeting the BPH problems [ 16 , 17 ].…”

Section: Resultsmentioning

confidence: 99%

Anti-Proliferative Effects of HBX-5 on Progression of Benign Prostatic Hyperplasia

et al. 2018

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Benign prostatic hyperplasia (BPH), an age-dependent disorder with a prevalence percentage of 60% in the 60s, has been found to involve an androgenic hormone imbalance that causes confusion between cell apoptosis and proliferation. Because general medications for BPH treatment have undesirable side effects, the development of effective alternative medicines has been considered. HBX-5 is a newly developed formula with the aim of improving BPH, and is composed of nine medicinal herbs. BPH was induced in the rats by intramuscular injection of testosterone propionate after castration. Rats were divided into six groups, and the efficacy of HBX-5 on testosterone-induced BPH in rats was estimated. In addition, RWPE-1 and WPMY-1 cells were used to demonstrate the effect of HBX-5 on BPH in vitro model. Compared with the control group, HBX-5 administration group suppressed BPH manifestations, such as excessive development of prostate, and increase of serum dihydrotestosterone and 5α-reductase concentrations. Furthermore, immunohistochemistry analysis revealed that HBX-5 significantly decreased the expression of androgen receptor (AR) and proliferating cell nuclear antigen (PCNA). In addition, results of RWPE-1 and WPMY-1 cells showed that HBX-5 inhibited the over-expression of AR and PSA in DHT-induced prostate hyperplastic microenvironments.

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Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms

Cited by 38 publications

References 35 publications

Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro

Berberine Improves Benign Prostatic Hyperplasia via Suppression of 5 Alpha Reductase and Extracellular Signal-Regulated Kinase in Vivo and in Vitro

Factors Driving Unique Urination Phenotypes of Male and Female 9-week-old C57BL/6J Mice

Anti-Proliferative Effects of HBX-5 on Progression of Benign Prostatic Hyperplasia

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