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1.  Intraprostatic injection of botulinum toxin type- A relieves bladder outlet obstruction in human and induces prostate apoptosis in dogs 
BMC Urology  2006;6:12.
Background
With the increasing interest with botulinum toxin – A (BTX-A) application in the lower urinary tract, we investigated the BTX-A effects on the canine prostate and also in men with bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH).
Methods
Transperineal injection into the prostate using transrectal ultrasound (TRUS) was performed throughout the study. Saline with or without 100 U of BTX-A was injected into mongrel dogs prostate. One or 3 months later, the prostate was harvested for morphologic and apoptotic study. In addition, eight BPH patients refractory to α-blockers were treated with ultrasound guided intraprostatic injection of 200 U of BTX-A.
Results
In the BTX-A treated dogs, atrophy and diffuse apoptosis was observed with H&E stain and TUNEL stain at 1 and 3 months. Clinically, the mean prostate volume, symptom score, and quality of life index were significantly reduced by 18.8%, 73.1%, and 61.5% respectively. Maximal flow rate significantly increased by 72.0%.
Conclusion
Intraprostatic BTX-A injection induces prostate apotosis in dogs and relieves BOO in humans. It is therefore a promising alternative treatment for refractory BOO due to BPH.
doi:10.1186/1471-2490-6-12
PMCID: PMC1481565  PMID: 16620393
2.  Intraprostatic Botulinum Toxin Type A injection in patients with benign prostatic enlargement: duration of the effect of a single treatment 
BMC Urology  2009;9:9.
Background
Botulinum Toxin Type-A (BoNT/A) intraprostatic injection can induce prostatic involution and improve LUTS and urinary flow in patients with Benign Prostatic Enlargement (BPE). However, the duration of these effects is unknown. The objective of this work was to determine the duration of prostate volume reduction after one single intraprostatic injection of 200U of Botulinum Toxin Type-A.
Methods
This is an extension of a 6 month study in which 21 frail elderly patients with refractory urinary retention and unfit for surgery were submitted to intraprostatic injection of BoNT/A-200U, by ultrasound guided transrectal approach. In spite of frail conditions, eleven patients could be followed during 18 months. Prostate volume, total serum PSA, maximal flow rate (Qmax), residual volume (PVR) and IPSS-QoL scores were determined at 1, 3, 6, 12 and 18 months post-treatment.
Results
Mean prostate volume at baseline, 82 ± 16 ml progressively decreased from month one coming to 49 ± 9,5 ml (p = 0,003) at month six. From this moment on, prostate volume slowly recovered, becoming identical to baseline at 18 months (73 ± 16 ml, p = 0.03). Albeit non significant, serum PSA showed a 25% decrease from baseline to month 6. The 11 patients resumed spontaneous voiding at month one. Mean Qmax was 11,3 ± 1,7 ml/sec and remained unchanged during the follow-up period. PVR ranged from 55 ± 17 to 82 ± 20 ml and IPSS score from10 to 12 points.
Conclusion
Intraprostatic BoNT/A injection is safe and can reduce prostate volume for a period of 18 months. During this time a marked symptomatic improvement can be maintained.
doi:10.1186/1471-2490-9-9
PMCID: PMC2734751  PMID: 19682392
3.  Comparison of Intraprostatic Ethanol Diffusion Using a Microporous Hollow Fiber Catheter Versus a Standard Needle 
The Journal of urology  2012;187(5):1898-1902.
Purpose
Transurethral intraprostatic ethanol chemoablation of the prostate has shown promising preliminary clinical results for benign prostatic hyperplasia with some variability in clinical outcome. This is likely due to the uneven prostate diffusion caused by varying resistance of the tissue type in which the tip of the needle is embedded. We examined whether the distribution of the injectable in the canine prostate could be improved using a microporous hollow fiber catheter (Twin Star Medical, Minneapolis, Minnesota).
Materials and Methods
The prostate was exposed in 9 mongrel dogs. A single injection of 98% ethanol was delivered in each lobe using a microporous hollow fiber catheter and a standard needle. Prostates were harvested and fixed in 10% formalin. After injection 2.5 mm step sections were obtained and scanned. The ethanol induced tissue lesions were traced on hematoxylin and eosin sections. Three-dimensional reconstructions were created and the volume of each prostate lesion was calculated using stereology.
Results
Ethanol induced tissue changes were seen bilaterally in 8 of 9 ethanol injected prostates. In all cases the lesion created by microporous hollow fiber catheter injection was larger than that in the contralateral lobe injected with the control needle. When data were pooled, the hollow fiber catheter injection produced significantly greater tissue changes than the control needle injection (p = 0.03).
Conclusions
Improved distribution and absent backflow were seen when using the microporous hollow fiber catheter, supporting its potential as a new method to treat prostate disease.
doi:10.1016/j.juro.2011.12.057
PMCID: PMC3730440  PMID: 22425049
prostate; injections; catheters; needles; instrumentation
4.  Evaluation of Short Term Clinical Effects and Presumptive Mechanism of Botulinum Toxin Type A as a Treatment Modality of Benign Prostatic Hyperplasia 
Yonsei Medical Journal  2006;47(5):706-714.
The purpose of this study was to evaluate the effect and investigate the putative mechanism of botulinum toxin type A (BTA) applied to the treatment of benign prostatic hyperplasia (BPH). A total of 52 patients with symptomatic BPH were evaluated. Transperineal intraprostatic injection under transrectal ultrasonography was carried out. BTA dissolved in 4 to 9 mL of saline was used from 100 U to 300 U, according to prostate volume. Twenty-six patients received only BTA (BT group), and 26 received both BTA and one month of an α-adrenergic antagonist (BTα group). The therapeutic outcomes were evaluated by comparing parameters such as international prostate symptom score (IPSS), quality of life, prostate specific antigen, prostate volume, post-void residual urine, and peak urinary flow rate. At the one month follow-up, 18 patients in the BT group and 21 in the BTα group had subjective symptomatic relief (p = 0.337). Only IPSS5 (weak stream) was significantly different between the BT group and BTα groups (p = 0.034). At the three month follow-up, 39 patients had subjective symptomatic relief. The storage symptoms were improved more than the voiding symptoms. Additionally, about 50 percent of the patients whose voiding symptom improved expressed improved erectile function. BTA injection seems to be an alternative treatment for BPH. The differences after the one month evaluation between the BT and the BTα groups might suggest that the adrenergic influence could be relatively reinforced by the anticholinergic effect of BTA. Nitric oxide would thus be involved in a BTA action mechanism in BPH.
doi:10.3349/ymj.2006.47.5.706
PMCID: PMC2687757  PMID: 17066515
Botulinum toxin type A; benign prostatic hyperplasia; neurotransmitter
5.  Chronic Prostatic Infection and Inflammation by Propionibacterium acnes in a Rat Prostate Infection Model 
PLoS ONE  2012;7(12):e51434.
Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.
doi:10.1371/journal.pone.0051434
PMCID: PMC3519880  PMID: 23240022
6.  Gene Expression Changes are Age-Dependent and Lobe-Specific in the Brown Norway Rat Model of Prostatic Hyperplasia 
The Prostate  2009;69(8):838-850.
Background
Benign prostatic hyperplasia (BPH) is an age-related enlargement of the prostate, characterized by increased proliferation of stromal and epithelial cells. Despite its prevalence, the etiology of BPH is unknown.
Methods
The Brown Norway rat is a model for age-dependent, lobe-specific hyperplasia of the prostate. Histological analyses of the dorsal and lateral lobes from aged rats reveal focal areas characterized by increased numbers of luminal epithelial cells, whereas the ventral lobe is unaffected. This study examined differential gene expression by lobe and age in the Brown Norway rat prostate. The objective was to identify genes with different levels of expression in the prostate lobes from 4-month (young) and 24-month (old) animals, and to subsequently link changes in gene expression to mechanisms of prostate aging.
Results
The number of age-dependent differentially expressed genes was greatest in the dorsal compared to the ventral and lateral lobes. Minimal redundancy was observed among the differentially expressed genes in the three lobes. Age-related changes in the expression levels of fourteen candidate genes in the dorsal, lateral and ventral lobes were confirmed by quantitative RT-PCR. Genes that exhibited age-related differences in their expression were associated with proliferation, oxidative stress, and prostate cancer progression, including topoisomerase II alpha (Topo2a), aurora kinase B (Aurkb), stathmin 1 (Stmn1), and glutathione S-transferase pi. Immunohistochemistry for Topo2a, Aurkb, and Stmn1 confirmed age-related changes in protein localization in the lateral lobe of young and aged prostates.
Conclusion
These findings provide clues to the molecular events associated with aging in the prostate.
doi:10.1002/pros.20935
PMCID: PMC2732361  PMID: 19204916
prostate; hyperplasia; age; microarray; gene expression
7.  Prospective, Randomized, Double-Blind, Vehicle Controlled, Multicenter Phase IIb Clinical Trial of the Pore Forming Protein PRX302 for Targeted Treatment of Symptomatic Benign Prostatic Hyperplasia 
The Journal of urology  2012;189(4):1421-1426.
Purpose
We conducted a safety and efficacy evaluation of intraprostatic injection of PRX302, a modified pore forming protein (proaerolysin) activated by prostate specific antigen, as a highly targeted, localized approach to treat lower urinary tract symptoms due to benign prostatic hyperplasia.
Materials and Methods
A total of 92 patients with I-PSS (International Prostate Symptom Score) 15 or greater, peak urine flow 12 ml or less per second and prostate volume 30 to 100 ml were randomized 2:1 to a single ultrasound guided intraprostatic injection of PRX302 vs vehicle (placebo) in this phase IIb double-blind study. Injection was 20% of prostate volume and 0.6 μg PRX302 per gm prostate. Peak urine flow was determined by a blinded reviewer. Benign prostatic hyperplasia medications were prohibited. The primary data set of efficacy evaluable patients (73) was analyzed using last observation carried forward.
Results
PRX302 treatment resulted in an approximate 9-point reduction in I-PSS and 3 ml per second increase in peak urine flow that were statistically significant changes from baseline compared to vehicle. Efficacy was sustained for 12 months. Early withdrawal for other benign prostatic hyperplasia treatment was more common for patients in the vehicle group. Relative to vehicle, PRX302 apparent toxicity was mild, transient, and limited to local discomfort/pain and irritative urinary symptoms occurring in the first few days, with no effect on erectile function.
Conclusions
A single administration of PRX302 as a short, outpatient based procedure was well tolerated in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. PRX302 produced clinically meaningful and statistically significant improvement in patient subjective (I-PSS) and quantitative objective (peak urine flow) measures sustained for 12 months. The side effect profile is favorable with most effects attributed to the injection itself and not related to drug toxicity.
doi:10.1016/j.juro.2012.11.003
PMCID: PMC3740739  PMID: 23142202
aerolysin; PRX302; prostatic hyperplasia; lower urinary tract symptoms
8.  Botulinum Neurotoxin Type A for the Treatment of Benign Prostatic Hyperplasia: Randomized Study Comparing Two Doses 
The Scientific World Journal  2012;2012:463574.
Purpose. To assess the efficacy and safety of intraprostatic injection of two botulinum neurotoxin type A (BoNT-A) doses for the treatment of benign prostatic hyperplasia (BPH). Materials and Methods. Men with symptomatic BPH who failed medical treatment were randomized to receive 100 U or 200 U of BoNT-A into the prostate. The International Prostatic Symptom Score (IPSS), maximum flow rate (Qmax), post-void residual volume (PVR), PSA levels and prostate volume before injection and after 3 and 6 months were evaluated. Adverse events were compared between the groups. Results. Thirty four patients were evaluated, including 17 in the BoNT-A 100 U group and 17 in the BoNT-A 200 U group. Baseline characteristics were similar in both groups. Both doses produced significant improvements in IPSS, Qmax and PVR after 3 and 6 months and both doses promoted comparable effects. Prostate volume was affected by 200 U BoNT-A injection only after 6 months of treatment. PSA levels were significantly affected in the 100 U group only after 6 months of treatment. In the 200 U group, PSA levels were significantly decreased after 3 and 6 months. The complication rate was similar in both groups. Conclusions. Efficacy and safety of both BoNT-A doses are similar for BPH treatment in the short term followup.
doi:10.1100/2012/463574
PMCID: PMC3446647  PMID: 22997495
9.  Development and Validation of an Animal Model of Prostate Inflammation-Induced Chronic Pelvic Pain: Evaluating from Inflammation of the Prostate to Pain Behavioral Modifications 
PLoS ONE  2014;9(5):e96824.
Background
Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is the most common type of prostatitis. Due to the lack of a suitable animal model partly, the pathogenesis for this condition is obscure. In the current study we developed and validated an animal model for nonbacterial prostatitis and prostate inflammation-induced chronic pelvic pain in rats with the use of intraprostatic injection of λ-carrageenan.
Methods
Male Sprague-Dawley rats weighing 250–350 g were used for the experiments. After intraprostatic injection of 3% λ-carrageenan, at different time points(after 24 h, 7d, 14d and 30d of injection), radiant heat and von Frey filaments were applied to the scrotum of rats to measure the heat and mechanical thresholds respectively. Then the prostate was removed for histology, and cyclooxygenase (COX) 2 protein expression was determined by Western-blot. Evans blue(50 mg/kg) was also injected intravenously to assess for plasma protein extravasation at different time points after injection of λ-carrageenan.
Results
Compared to control group, inflamed animals showed a significant reduction in mechanical threshold (mechanical allodynia) at 24 h and 7d(p = 0.022,0.046, respectively), and a significant reduction in heat threshold (thermal hyperalgesia) at 24 h, 7d and 14d(p = 0.014, 0.018, 0.002, respectively) in the scrotal skin. Significant increase of inflammatory cell accumulation,COX2 expression and Evans blue extravasation were observed at 24 h, 7d and 14d after injection.
Conclusions
Intraprostatic λ-carrageenan injection induced neurogenic prostatitis and prostate inflammation pain, which lasted at least 2 weeks. The current model is expected to be a valuable preclinical tool to study the neurobiological mechanisms of male chronic pelvic pain.
doi:10.1371/journal.pone.0096824
PMCID: PMC4019557  PMID: 24823660
10.  Neuroprotective Effects of MicroRNA-210 on Hypoxic-Ischemic Encephalopathy 
BioMed Research International  2013;2013:350419.
Objectives. To reveal the effect of microRNA-210 on cell apoptosis caused by HIE. Methods. Postnatal day 7 rats after HI injury were intraventricularly injected with microRNA-210 mimic, microRNA-210 inhibitor, or physiological saline. 72 h after the injection, rats were sacrificed and the left hemispheres were collected. The expression level of microRNA-210 was identified by quantitative real-time PCR analysis. Apoptosis in brain sections was investigated by TUNEL assay. Apoptosis-related protein expressions were studied by Western blot analysis. Results. The results showed that microRNA-210, whose expression was downregulated in the brain 72 h after HI injury, suppressed neuronal apoptosis by inhibiting caspase activity and regulating the balance between bcl-2 and bax levels. Discussion. Recent study demonstrated that microRNA-210 has neuroprotective effects through inhibiting apoptosis in a murine model of HIE. It represents a potential novel therapeutic approach for the treatment of HIE.
doi:10.1155/2013/350419
PMCID: PMC3782121  PMID: 24089674
11.  Injection therapy for prostatic disease: A renaissance concept 
Purpose:
Initially conceived as an intervention for prostatic infection, injection therapy has been used to alleviate urinary retention, and is now primarily investigated for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). For over a century, intraprostatic injection has been used as a minimally invasive surgical therapy (MIST), and is on the verge of a rebirth. This review will familiarize the reader with the origins and history of intraprostatic injection, and its evolution using transperineal, transrectal and transurethral routes with multiple injectants.
Materials and Methods:
A MEDLINE review of the literature on intraprostatic injections published between 1966 and 2007 was performed, augmented with articles and documents dating back to 1832.
Results:
Transperineal and transurethral injections have the most systematic evaluation in patients. There are advantages and disadvantages associated with each route. Most injectants consistently produce localized coagulative necrosis and gland volume reduction with varying degrees of LUTS relief. Anhydrous ethanol (AE) is the most extensively studied injected agent to date.
Conclusions:
Injection therapy is a promising minimally invasive treatment option for various prostatic conditions and has been examined for over 100 years. Further experience in systematic laboratory research and completion of currently ongoing clinical trials is necessary before widespread clinical application.
doi:10.4103/0970-1591.42613
PMCID: PMC2684358  PMID: 19468462
Benign prostatic hyperplasia; injection; prostatic disease; prostate
12.  Inhibitory effect of rape pollen supercritical CO2 fluid extract against testosterone-induced benign prostatic hyperplasia in rats 
Benign prostatic hyperplasia (BPH) can lead to lower urinary tract symptoms. Rape pollen is an apicultural product that is composed of nutritionally valuable and biologically active substances. The aim of the present study was to investigate the protective effect of rape pollen supercritical CO2 fluid extract (SFE-CO2) in BPH development using a testosterone-induced BPH rat model. BPH was induced in the experimental groups by daily subcutaneous injections of testosterone for a period of 30 days. Rape pollen SFE-CO2 was administered daily by oral gavage concurrently with the testosterone injections. Animals were sacrificed at the scheduled termination and the prostates were weighed and subjected to histopathological examination. Testosterone, dihydrotestosterone (DHT), 5α-reductase and cyclooxygenase-2 (COX-2) levels were also measured. BPH-induced animals exhibited an increase in prostate weight with increased testosterone, DHT, 5α-reductase and COX-2 expression levels. However, rape pollen SFE-CO2 treatment resulted in significant reductions in the prostate index and testosterone, DHT, 5α-reductase and COX-2 levels compared with those in BPH-induced animals. Histopathological examination also demonstrated that rape pollen SFE-CO2 treatment suppressed testosterone-induced BPH. These observations indicate that rape pollen SFE-CO2 inhibits the development of BPH in rats and these effects are closely associated with reductions in DHT, 5α-reductase and COX-2 levels. Therefore, the results of the present study clearly indicate that rape pollen SFE-CO2 extract may be a useful agent in BPH treatment.
doi:10.3892/etm.2014.1680
PMCID: PMC4061240  PMID: 24944593
rape pollen; benign prostatic hyperplasia; 5α-reductase; cyclooxygenase-2
13.  Inhibitory effects by ayurvedic plants on prostate enlargement induced in rats 
Pharmacognosy Research  2014;6(2):127-132.
Background:
Ayurveda recommends several plants and plant preparation for conditions of urogenital disorders as per its principles. Objectives: Ayurvedic plants Tamala (Cinnamomum tamala); Daruhalad (Berberis aristata); Ativish (Aconitum heterophyllum) were studied for mechanisms of prostatic hyperplasia induced in rats.
Materials and Methods:
Prostatic enlargement was induced in castrated rats by testosterone injection s.c. for 21 days and simultaneously plants were dosed orally daily. On day 22 rats were sacrificed and prostate was removed; weight and volume of prostate was measured; histopathology performed. Inflammation was induced by injecting carrageenan in rat hind paw and inhibition was studied by measuring rat paw oedema at different time points.
Results:
Tamala showed significant effect where it reduced prostatic enlargement and improved hyperplastic changes, while Daruhalad and Ativisha did not show any significant effect. All of them showed mild to moderate anti-inflammatory activity.
Conclusion:
Study concludes that Tamala may benefit in prostate disorder by virtue of inhibition of androgen mechanisms in prostate and modulating inflammatory mediators in prostate. Daruhalad and Ativisha did not show any effect in this model of prostate enlargement while the anti-inflammatory effect may propose one of the useful properties when included in various formulations.
doi:10.4103/0974-8490.129031
PMCID: PMC3996748  PMID: 24761116
Ativisha (Aconitum heterophyllum); daruhalad (Berberis aristata); prostatic hyperplasia; tamala (Cinnamomum tamala)
14.  Phase 1 and 2 Studies Demonstrate the Safety and Efficacy of Intraprostatic Injection of PRX302 for the Targeted Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia 
European urology  2010;59(5):747-754.
Background
PRX302 is a prostate specific antigen (PSA)–activated pore-forming protein toxin under development as a targeted approach for improving lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) without affecting sexual function.
Objective
To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH.
Design, setting, and participants
Eligible subjects were refractory, intolerant, or unwilling to undergo medical therapies for BPH and had International Prostate Symptom Score (IPSS) ≥12, a quality of life (QoL) score ≥3, and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies.
Interventions
Subjects received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 subjects received increasing concentrations of PRX302 at a fixed volume; phase 2 subjects received increasing volumes per deposit at a fixed concentration.
Measurements
IPSS, QoL, prostate volume, maximum flow rate (Qmax), International Index of Erectile Function, serum PSA levels, pharmacokinetics, and adverse events were recorded at 30, 60, 90, 180, 270, and 360 d after treatment with PRX302.
Results and limitations
Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had ≥30% improvement compared to baseline in IPSS out to day 360. Patients also experienced improvement in QoL and reduction in prostate volume out to day 360. Patients receiving ≥1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size.
Conclusions
The promising safety profile and evidence of efficacy in the majority of treated subjects in these phase 1 and 2 studies supports further development of PRX302 as a minimally invasive, targeted treatment for BPH.
doi:10.1016/j.eururo.2010.11.024
PMCID: PMC3454506  PMID: 21129846
Benign prostatic hyperplasia; Intraprostatic; Lower urinary tract symptoms; Proaerolysin; Prostate-specific antigen; Protease; Protein toxin
15.  Effect of Boerhaavia diffusa in experimental prostatic hyperplasia in rats 
Indian Journal of Pharmacology  2013;45(3):264-269.
Objective:
Present investigation was undertaken to study the effectiveness of hydroalcoholic extract of roots of Boerhaavia diffusa in experimental benign prostatic hyperplasia (BPH) in rats using various animal models.
Materials and Methods:
BPH in rats was induced by subcutaneous injection of testosterone (5 mg/kg) daily for 28 days. Rats were divided in to five groups (six rats each). A negative control group received arachis oil (1 ml/kg s.c.) and four groups were injected testosterone. These four groups were further divided into reference group (finasteride 1 mg/kg), model group (testosterone), study group A (B. diffusa 100 mg/kg), and study group B (B. diffusa 250 mg/kg). On the 29th day, rats were sacrificed and body weight, prostate weight, bladder weight, and serum testosterone level were measured and histological studies were carried out. Further in vitro analysis of B. diffusa extract on contractility of isolated rat vas deferens and prostate gland, produced by exogenously administered agonists were carried out. All results were expressed as mean ± SEM. 0 Data were analyzed by one-way analysis of variance followed by Tukey's test.
Results:
B. diffusa (100 mg/kg) treatment for 28 days resulted in significant inhibition of prostate growth (P < 0.05). Drug extract did not have significant change on serum testosterone level. Histopathological analysis of prostate gland supported above results. Results of in vitro experiment suggest that extracts had attenuated the contractile responses of isolated vas deferens and prostate gland to exogenously applied agonists.
Conclusion:
The results suggested that treatment with B. diffusa may improve symptoms of disease and inhibit the increased prostate size. In vitro study implies that herbal extracts has the machinery to produce beneficial effect on prostatic smooth muscle, which would relieve the urinary symptoms of disease. B. diffusa could be a potential source of new treatment of prostatic hyperplasia.
doi:10.4103/0253-7613.111946
PMCID: PMC3696298  PMID: 23833370
Benign prostatic hyperplasia; Boerhaavia diffusa; dihydrotestosterone; isolated vas deferens; prostate gland; testosterone
16.  Proliferation and phenotypic changes of stromal cells in response to varying estrogen/androgen levels in castrated rats 
Asian Journal of Andrology  2009;11(4):451-459.
It is known that human benign prostatic hyperplasia might arise from an estrogen/androgen (E/T) imbalance. We studied the response of castrated rat prostate to different ratios of circulating E/T. The castrated male Wistar rats were randomly injected with E/T at different ratios for 4 weeks. The prostates of E/T (1:100) group showed a distinct prostatic hyperplasia response by prostatic index, hematoxylin and eosin staining, and quantitative immunohistochemical analysis of α-smooth muscle actin (SMA). In this group, cells positive for Vimentin, non-muscle myosin heavy chain (NMMHC) and proliferating cell nuclear antigen (PCNA) increased in the stroma and epithelium. Furthermore, the mRNA levels of smooth muscle myosin heavy chain (SMMHC) and NMMHC increased. So E/T at a ratio of 1:100 can induce a stromal hyperplastic response in the prostate of castrated rats. The main change observed was an increase of smooth muscle cells, whereas some epithelial changes were also seen in the rat prostates.
doi:10.1038/aja.2009.28
PMCID: PMC3735307  PMID: 19483715
androgens; castration; estrogen; prostatic hyperplasia; rat; stromal cells
17.  Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro 
The merit of opioid μ-receptor activation in the improvement of benign prostatic hyperplasia (BPH) remains obscure. In the present study, we used loperamide to identify the subtype of opioid μ-receptors involved in prostatic relaxation and investigate the possible mechanism of this relaxation. Prostate strips were isolated from 12-week-old male Wistar rats for identification of isometric tension. The prostate strips were precontracted with either 1 μmol/l phenylephrine or 50 mmol/l KCl. The decrease in muscle tone (relaxation) was then characterized after cumulative administration of loperamide (0.1 to 10 μmol/l) into the organ bath for the concentration-dependent study. Pretreatment with specific blockers or antagonists was carried out to compare the changes in loperamide-induced relaxation. Loperamide produced a marked relaxation in the isolated prostates precontracted with phenylephrine or KCl in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid μ-receptor antagonist, but was not modified by naloxonazine at a dose sufficient to block the opioid μ-1 receptors. Treatment with an agonist for opioid μ-1 receptors also failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K+ channels. In addition, this action of loperamide was abolished by protein kinase A (PKA) inhibitor and enhanced by the inhibitor of phosphodiesterase for cyclic AMP (cAMP). Our results suggest that loperamide induces prostatic relaxation through activation of opioid μ-2 receptors via the cAMP-PKA pathway to open ATP-sensitive K+ channels.
doi:10.3892/etm.2011.201
PMCID: PMC3440672  PMID: 22977498
ATP-sensitive K+ channels; isometric tension; loperamide; μ-opioid receptors; rat prostate
18.  Pharmacotherapy for benign prostatic hyperplasia. 
Western Journal of Medicine  1994;161(5):495-506.
Benign prostatic hyperplasia is a benign neoplasm of the prostate seen in men of advancing age. Microscopic evidence of the disorder is seen in about 70% of men by 70 years of age, whereas symptoms requiring some form of surgical intervention occur in 30% of men during their lifetime. Although the exact cause of benign prostatic hyperplasia is not clear, it is well recognized that high levels of intraprostatic androgens are required for the maintenance of prostatic growth. In recent years, extensive surveys of patients undergoing transurethral resection of the prostate reveal an 18% incidence of morbidity that has essentially not changed in the past 30 years. This procedure is also the second highest reimbursed surgical therapy under Medicare. These findings have resulted in an intensive search for alternative therapies for prostatic hyperplasia. An alternative that has now been well defined is the use of alpha-adrenergic blockers to relax the prostatic urethra. This is based on findings that a major component of benign prostatic hyperplasia symptoms is spasm of the prostatic urethra and bladder neck, which is mediated by the alpha-adrenergic nerves. A second approach is to block androgens involved in maintaining prostate growth. Several such drugs are now available for clinical use, and we discuss their side effects and use. We also include the newer recommendations on evaluating benign prostatic hyperplasia that are cost-effective yet comprehensive.
Images
PMCID: PMC1022678  PMID: 7528957
19.  Effects of Melandrium firmum methanolic extract on testosterone-induced benign prostatic hyperplasia in Wistar rats 
Asian Journal of Andrology  2012;14(2):320-324.
Benign prostatic hyperplasia (BPH) is an age-related disease of unknown aetiology characterized by prostatic enlargement coincident with distinct alterations in tissue histomorphology. Instead of therapeutic agents that can cause severe side effects, plant extracts are frequently used to treat BPH. In this study, we investigated whether the Melandrium firmum methanolic extract (MFME) improves BPH, using the testosterone propionate (TP)-induced BPH rat model. Castration was performed via the scrotal route under sodium pentobarbital anaesthesia. BPH in castrated rats was generated via daily subcutaneous injections of TP (3 mg kg−1) dissolved in corn oil, for 4 weeks. MFME was administered daily by oral gavage at a dose of 200 mg kg−1 for 4 weeks, along with the TP injections. The control group received injections of corn oil subcutaneously. At the scheduled termination of the experiment, all rats were killed and their prostates weighed; the relative prostate weight (prostate/body weight ratio) was calculated, and histomorphological changes in the prostate were examined. Additionally, we measured the levels of testosterone and dihydrotestosterone (DHT) in the serum and the prostate. Experimentally induced BPH led to marked decreases in the relative prostate weight and the DHT levels in the serum and the prostate. Histologically, BPH was evident in the ventral lobe of the prostate, and MFME treatment suppressed the severity of the lesions. These results indicate that MFME effectively inhibits the development of BPH induced by testosterone in a rat model. Further studies will be needed to identify the compound(s) responsibility for inducing the protective effect against BPH and determine its mechanism of action.
doi:10.1038/aja.2011.166
PMCID: PMC3735082  PMID: 22231294
benign prostatic hyperplasia; dihydrotestosterone; Melandrium firmum (S. et Z.)ROHRB; prostate; testosterone
20.  Influence of acute pancreatitis on the in vitro responsiveness of rat mesenteric and pulmonary arteries 
BMC Gastroenterology  2008;8:19.
Background
Acute pancreatitis is an inflammatory disease characterized by local tissue injury and systemic inflammatory response leading to massive nitric oxide (NO) production and haemodynamic disturbances. Therefore, the aim of this work was to evaluate the vascular reactivity of pulmonary and mesenteric artery rings from rats submitted to experimental pancreatitis.
Male Wistar rats were divided into three groups: saline (SAL); tauracholate (TAU) and phospholipase A2 (PLA2). Pancreatitis was induced by administration of TAU or PLA2 from Naja mocambique mocambique into the common bile duct of rats, and after 4 h of duct injection the animals were sacrificed. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP) and phenylephrine (PHE) in isolated mesenteric and pulmonary arteries were obtained. Potency (pEC50) and maximal responses (EMAX) were determined. Blood samples were collected for biochemical analysis.
Results
In mesenteric rings, the potency for ACh was significantly decreased from animals treated with TAU (about 4.2-fold) or PLA2 (about 6.9-fold) compared to saline group without changes in the maximal responses. Neither pEC50 nor EMAX values for Ach were altered in pulmonary rings in any group. Similarly, the pEC50 and the EMAX values for SNP were not changed in both preparations in any group. The potency for PHE was significantly decreased in rat mesenteric and pulmonary rings from TAU group compared to SAL group (about 2.2- and 2.69-fold, for mesenteric and pulmonary rings, respectively). No changes were seen in the EMAX for PHE. The nitrite/nitrate (NOx-) levels were markedly increased in animals submitted to acute pancreatitis as compared to SAL group, approximately 76 and 68% in TAU and PLA2 protocol, respectively.
Conclusion
Acute pancreatitis provoked deleterious effects in endothelium-dependent relaxing response for ACh in mesenteric rings that were strongly associated with high plasma NOx- levels as consequence of intense inflammatory responses. Furthermore, the subsensitivity of contractile response to PHE in both mesenteric and pulmonary rings might be due to the complications of this pathological condition in the early stage of pancreatitis.
doi:10.1186/1471-230X-8-19
PMCID: PMC2435530  PMID: 18510740
21.  Nerve growth factor signaling following unilateral pelvic ganglionectomy in the rat ventral prostate is age dependent 
Asian Journal of Andrology  2013;15(6):764-769.
Benign prostatic hyperplasia (BPH) is a serious health concern and is an underlying cause of lower urinary tract symptoms (LUTS) in many men. In affected men, LUTS/BPH is believed to result from benign proliferation of the prostate resulting in bladder outlet obstruction. Postnatal growth of the prostate is controlled via growth factor and endocrine mechanisms. However, little attention had been given to the function of the autonomic nervous system in prostate growth and differentiation. Nerve growth factor (NGF) is a prostatic mitogen that has a trophic role in autonomic sensory end organ interaction. In this study, we examine how the autonomic nervous system influences prostate growth as a function of age by quantifying NGF in the rat ventral prostate (VP) after pelvic ganglionectomy. Unilateral pelvic ganglionectomy was performed on postnatal days 30 (P30), 60 and 120 Sprague–Dawley rats in comparison to sham controls (n=39). Semiquantitative RT-PCR, Western blotting and immunohistochemical analysis for NGF were performed on denervated, intact (contralateral side) and sham control VP 7 days after surgery. Ngf RNA expression was significantly increased in the denervated and intact hyperplastic VP. Western blotting showed age-dependent increases in NGF protein at P60 in the contralateral intact VP. NGF was localized in the nerves, basal cells and columnar epithelium of the prostatic ducts. Denervation causes age-dependent increases in NGF in the VP, which is a potential mechanism by which the autonomic nervous system may regulate prostate growth and lead to BPH/LUTS.
doi:10.1038/aja.2013.59
PMCID: PMC3854044  PMID: 23872662
denervation; nerve growth factor; prostate growth; ventral prostate
22.  Inhibitors of apoptosis proteins in experimental benign prostatic hyperplasia: effects of serenoa repens, selenium and lycopene 
Background
The apoptosis machinery is a promising target against benign prostatic hyperplasia (BPH). Inhibitors of apoptosis proteins (IAPs) modulate apoptosis by direct inhibition of caspases. Serenoa Repens (SeR) may be combined with other natural compounds such as Lycopene (Ly) and Selenium (Se) to maximize its therapeutic activity in BPH. We investigated the effects of SeR, Se and Ly, alone or in association, on the expression of four IAPs, cIAP-1, cIAP-2, NAIP and survivin in rats with experimental testosterone-dependent BPH. Moreover, caspase-3, interleukin-6 (IL-6) and prostate specific membrane antigen (PSMA) have been evaluated.
Rats were administered, daily, with testosterone propionate (3 mg/kg/sc) or its vehicle for 14 days. Testosterone injected animals (BPH) were randomized to receive vehicle, SeR (25 mg/kg/sc), Se (3 mg/kg/sc), Ly (1 mg/kg/sc) or the SeR-Se-Ly association for 14 days. Animals were sacrificed and prostate removed for analysis.
Results
BPH animals treated with vehicle showed unchanged expression of cIAP-1 and cIAP-2 and increased expression of NAIP, survivin, caspase-3, IL-6 and PSMA levels when compared with sham animals. Immunofluorescence studies confirmed the enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization. SeR-Se-Ly association showed the highest efficacy in reawakening apoptosis; additionally, this therapeutic cocktail significantly reduced IL-6 and PSMA levels. The administration of SeR, Se and Ly significantly blunted prostate overweight and growth; moreover, the SeR-Se-Ly association was most effective in reducing prostate enlargement and growth by 43.3% in treated animals.
Conclusions
The results indicate that IAPs may represent interesting targets for drug therapy of BPH.
doi:10.1186/1423-0127-21-19
PMCID: PMC3995880  PMID: 24606563
Apoptosis; BPH; IAPs; Lycopene; Selenium; Serenoa Repens
23.  Expression and Function of the Human Androgen-Responsive Gene ADI1 in Prostate Cancer1 
Neoplasia (New York, N.Y.)  2007;9(8):643-651.
We have previously identified an androgen-responsive gene in rat prostate that shares homology with the aci-reductone dioxygenase (ARD/ARD′) family of metal-binding enzymes involved in methionine salvage. We found that the gene, aci-reductone dioxygenase 1 (ADI1), was downregulated in prostate cancer cells, whereas enforced expression of rat Adi1 in these cells caused apoptosis. Here we report the characterization of human ADI1 in prostate cancer. Androgens induced ADI1 expression in human prostate cancer LNCaP cells, which was not blocked by cycloheximide, indicating that ADI1 is a primary androgen-responsive gene. In human benign prostatic hyperplasia specimens, epithelial cells expressed ADI1. Immunohistochemistry of prostate tumor tissue microarrays showed that benign regions expressed more ADI1 than tumors, suggesting a suppressive role for ADI1 in prostate cancer. Bacterial lysates containing recombinant ADI1 produced a five-fold increase in aci-reductone decay over controls, demonstrating that ADI1 has ARD activity. We generated point mutations at key residues in the metal-binding site of ADI1 to disrupt ARD function, and we found that these mutations did not affect intracellular localization, apoptosis, or colony formation suppression in human prostate cancer cells. Collectively, these observations argue that ADI1 may check prostate cancer progression through apoptosis and that this activity does not require metal binding.
PMCID: PMC1950434  PMID: 17786183
ADI1; androgen-responsive gene; prostate cancer; aci-reductone dioxygenase; apoptosis
24.  Qianliening capsule inhibits benign prostatic hyperplasia angiogenesis via the HIF-1α signaling pathway 
Angiogenesis plays an important role in the progression and development of benign prostatic hyperplasia (BPH), and has become a promising target for BPH treatment. The hypoxia-inducible factor-1α (HIF-1α) signaling pathway promotes the process of angiogenesis, contributing to the growth and progression of a number of hyperplasia diseases, including BPH. Qianliening capsule (QC) is a traditional Chinese formula that has been used clinically in China to treat BPH for a number of years. Recently, QC was demonstrated to inhibit prostatic cell growth and induce apoptosis in vivo and in vitro via regulating the epidermal growth factor/signal transducer and activator of transcription 3 signaling pathway and mitochondrion-dependent apoptosis pathway. However, the mechanisms underlying the anti-BPH effect remain largely unknown. To further elucidate the mechanism of QC activity in BPH treatment, a rat BPH model established by injecting testosterone following castration was established and the effect of QC on prostatic tissue angiogenesis was evaluated, as well as the underlying molecular mechanisms. QC was shown to reduce the prostatic index in BPH rats, but without affecting the body weight, demonstrating that QC is effective in the treatment of BPH and without apparent toxicity. In addition, QC treatment significantly reduced the intraprostatic microvessel density, indicating antiangiogenesis activity in vivo. In addition, treatment with QC inhibited the expression of HIF-1α in BPH rats, as well as the expression of vascular endothelial growth factor and basic fibroblast growth factor. Therefore, for the first time, the present study hypothesized that QC inhibits angiogenesis in prostatic tissue of BPH rats via the inhibition of the HIF-1α signaling pathway, which may be one of the mechanisms in which QC treats BPH.
doi:10.3892/etm.2014.1723
PMCID: PMC4061199  PMID: 24944609
qianliening capsule; benign prostatic hyperplasia; angiogenesis; hypoxia-inducible factor-1α; vascular endothelial growth factor; basic fibroblast growth factor
25.  Seoritae Extract Reduces Prostate Weight and Suppresses Prostate Cell Proliferation in a Rat Model of Benign Prostate Hyperplasia 
Seoritae is a type of black soybean that is known to have health-promoting effects due to its high isoflavone and anthocyanin contents. We evaluated whether Seoritae extract (SE) had beneficial effects on the reduction of prostate weight in a rat model of benign prostatic hyperplasia (BPH). BPH was induced by intramuscular injections of testosterone enanthate once a week for 5 weeks in Sprague-Dawley rats, and rats were treated with or without daily oral doses of SE during BPH induction. After 5 weeks, the oxidative stress (superoxide dismutase and 8-hydroxy-2-deoxyguanosine), apoptosis (caspase-3), and activity of 5-alpha reductase were evaluated in the serum and prostate. The SE treatment group showed a significant decrease in prostate weight, oxidative stress, apoptosis, and 5-alpha reductase activity compared to the nontreated BPH group. These results show that SE is effective in decreasing the weight and proliferation of the prostate, and suggest that SE may be an effective treatment for BPH.
doi:10.1155/2014/475876
PMCID: PMC3950473  PMID: 24701239

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