Neuroendocrine Cells and Peptidergic Innervation in Human and Rat Prostrate

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Avtor ji. Image analysis and stereology. Serotonin immunoreactive neuroendocrine cells and peptidergic nerves NPY and VIP could have a role in prostate growth and function. For this reason, we first tested the hypothesis that 5-HT could regulate prostate growth using in vitro cultures of rat ventral prostate explants VPs from P1 newborns.

During 4 days in culture, 5-HT supplementation induced a significant dose-dependent inhibition of rat VPs growth Fig. As expected, testosterone supplementation of VPs exerted a strong stimulatory effect on prostate branching morphogenesis, mainly in the number of peripheral buds Fig. Error bars indicate s.

Neuroendocrine Cells and Peptidergic Innervation in Human and Rat Prostate

From all 5-HT receptors, 5-Htr1a and 5-Htr1b were the most extensively studied in the regulation of malignant prostate growth 23 , 24 , so we tested if these receptors could contribute to the 5-HT inhibitory function in normal prostate growth. By immunofluorescence, we found that both receptors are strongly expressed in rat prostate but with a slightly different distribution pattern with 5-Htr1a predominantly expressed in prostate epithelium Fig.

To determine the contribution of both receptors in 5-HT inhibition of prostate branching morphogenesis, VPs were treated with drugs that specifically activate 5-Htr1a or 5-Htr1b. Since, androgens are a major prostatic stimulatory factor, we asked if the 5-HT inhibitory effect was related to the AR stimulatory pathway. By western blot analysis we showed that testosterone supplementation induced AR up-regulation, but 5-HT treatment significantly decreased AR expression either with or without testosterone supplementation Fig. Taken together these results indicate that in vitro 5-HT inhibits rat prostate growth through 5-Htr1a and 5-Htr1b , by down-regulating AR.

Next, we asked if this mechanism is also present in human prostate. First, we showed that both receptors are expressed in the three human prostate cell lines Fig. Similarly, both specific agonists of 5-Htr1a and 5-Htr1b strongly inhibited cell proliferation Fig. Next, we investigated if this inhibitory function of 5-HT, 5-Htr1a and 5-Htr1b specific agonists was related to changes in the AR pathway.

Additionally, by immunofluorescence analysis we observed that expression of AR after testosterone treatment was decreased in BPH-1 cells treated with 5-HT, 5-Htr1a and 5-Htr1b specific agonists Supplementary Fig. Full, uncropped gel images are shown. AR, androgen receptor; 5-HT, serotonin. Remarkably, the absence of inhibitory action of 5-HT, 5-Htr1a and 5-Htr1b specific agonists on PNT1A cells viability and proliferation, even in presence of testosterone, co-existed with a complete absence of AR expression in these cells Fig.

Tph type 1 Tph1 and 2 Tph2 regulate 5-HT production in non-neuronal and neuronal tissues, respectively 25 , The majority of 5-HT in the body is produced by Tph1. Genetic deletion of Tph1 increases prostate gland mass.

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H,I Student t test. It is well established that castration induces a strong reduction in size of the prostate gland as well as in seminal vesicles, while testosterone supplementation makes both organs return to normal size 27 , Currently, the etiology of BPH is unknown. However, it is accepted today that BPH is a consequence of aging and the simultaneous presence of testosterone 3.

BPH almost universally affects human males and a significant part of men will develop bothersome LUTS because of benign prostate enlargement. In this study, we investigated the function of 5-HT in the regulation of non-malignant prostatic growth. Here, we demonstrated for the first time in several in vitro and in vivo models that 5-HT is a powerful negative regulator of prostatic growth through down-regulation of AR.

We found that 5-Htr1a and 5-Htr1b are strongly expressed in the rodent prostate gland as well in human benign prostate cells, and that both receptors could mediate the inhibitory action of 5-HT on prostate growth. Our in vitro and animal findings lead us to propose a new mechanism to explain the development of BPH in humans Fig. Our proposed model explains how the depletion of neuroendocrine cells and serotonin observed in prostatic transition zone with aging 18 , 19 , 20 , could be the etiologic factor responsible for the initiation and progression of BPH.

In our model, the depletion of serotonin induces an up-regulation of androgen receptor in the prostatic transition zone leading to the stimulation of benign prostatic growth in this specific prostatic region. Neuroendocrine hypothesis for etiopathogenesis of benign prostatic hyperplasia. Serotonin is secreted to the epithelium-stroma interface and through activation of 5-Htr1a and 5-Htr1b , both in epithelium and stroma, the expression of AR is decreased. Yet, more testosterone is delivery to prostate, down-regulated AR limits benign prostate growth.

As a consequence 5-Htr1a and 5-Htr1b release their inhibition over AR expression. Although with aging the delivery of testosterone to the prostate is decreased the up-regulation of AR induces the development of BPH. Our neuroendocrine model for the etiopathogenesis of BPH would resolve an intriguing question about the crucial participation of androgens in the development of BPH.

Previous studies have showed that testosterone does not increase with aging and some studies have even reported that plasmatic testosterone is decreased in the aging human male 9 , 10 , In a similar way, intraprostatic testosterone, in particular DHT, are not increased in BPH comparatively to normal prostate 30 and even the administration of testosterone in supra-physiologic concentrations to eugonadal men does not induce the development of BPH 31 , This data were the basis for the saturation model of prostate growth proposed by Morgentaler et al. The critical point, in saturation model is that the rate-limiting step for prostatic growth, which is the concentration of AR.


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Recent studies demonstrated that AR is in fact up-regulated in stroma and epithelium of BPH tissue comparatively to normal prostate, implicating AR in etiophatogenesis of BPH 13 , 14 , Our findings seem to provide an explanation for this current view about the participation of androgens in the development of BPH. In this way, the loss of neuroendocrine cells and serotonin in prostatic transition zone up-regulates the AR and then permits the development of BPH, even with a decreased plasmatic concentration of androgens observed in the aging male. Our first in vitro experimental approach focused on the function of 5-HT in the regulation of rat prostate branching morphogenesis.

Because BPH is the result of new branching morphogenesis, this model permits the study the influence of 5-HT exactly in the mechanism by which BPH develops and progresses. Here, we demonstrate that 5-HT strongly inhibit the branching morphogenesis of the prostate gland through down-regulation of AR. In fact, other organs like the prostate which have a development process of branching morphogenesis, such as the mammary gland, 5-HT also have demonstrated a development inhibitory action Although new in the prostate gland, the serotoninergic inhibitory mechanism through down-regulation of AR, is well known in the brain.

In fact, the complete masculinization of the brain is dependent of a perinatal surge of testosterone and a simultaneous decrease in hypothalamic 5-HT concentrations In the brain, it has been demonstrated that regulation of 5-HT concentration is crucial for normal sexual differentiation, where 5-HT down-regulates AR 35 , In agreement with our findings, Sayed et al. However, both in brain and prostate the full mechanism responsible for this down-regulation remains to be elucidated. The most described 5-HT receptors in prostatic cells, are the 5-Htr1a and 5-Htr1b.

Therefore, we characterize its expression in rat prostate for the first time. As we demonstrated both 5-Htr1a and 5-Htr1b are strongly expressed in rat prostate and the activation of these receptors resulted in a significant inhibition of prostate branching morphogenesis, which also occurred through down-regulation of AR.

In human prostatic cells the function of 5-HT, 5-Htr1a , and 5-Htr1b have been previously studied but only in malignant cells 23 , These previous reports showed that 5-HT has a proliferative effect in several malignant cell lines through 5-Htr1a and 5-Htr1b. Curiously, this stimulatory effect was mainly evident in androgen-insensitive cells Here we studied, for the first time, the function of 5-HT, 5-Htr1a , and 5-Htr1b in human benign prostatic cells.

References

We demonstrated that 5-HT inhibits proliferation of androgen sensitive benign prostatic cells, and this inhibitory function was associated to a down-regulation of AR. This different growth function of 5-HT in benign and malignant cells remains unexplained but the predominant stimulatory effect of 5-HT in androgen-insensitive malignant cells suggests that castration resistance could change the phenotypic response of prostatic cell to neuroendocrine products.

Finally, to test in vivo our mechanistic approach to the etiopathogenesis of BPH, we genetically ablated the peripheral production of 5-HT. The inhibition of peripheral 5-HT synthesis in mice, through genetic deletion of Tph1, simulates a decrease in the prostate transition zone 5-HT observed in the aging male. This led us to propose that the decrease in neuroendocrine cells and 5-HT in the human transition zone could contribute to the development of BPH.

In conclusion, our findings suggest that 5-HT is a strong negative regulator of prostate growth through AR down-regulation.

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Therefore, this new described serotoninergic inhibitory pathway over benign prostatic growth should be explored as a new target for BPH treatment. Newborn male Sprague-Dawley rats were sacrificed hours after birth. Ventral prostate lobes were microdissected using a stereomicroscope Leica MZ6, Switzerland and processed for organ culture.

Rat Poison - Punctured Prostate Gland

Organ culture was performed as previously described Branching morphogenesis in all groups was monitored daily by a stereomicroscope and photographs were taken at day 0 and day 4. The number of peripheral buds was manually counted and the prostate tissue area was measured in ImageJ using the beProstate plugin Version 1.


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For each experimental group a dose-effect approach was used. For the proliferation assay, we evaluated the number of Ki positive cells by immunofluorescence. The total number of cells and the Ki positive cells were manual counted using a fluorescence microscopy BX16; Olympus. The ratio of Ki positive cells per total number of cells was determined, and the final results were expressed in relation to the control adjusted to 1. Only male mice were used for in vivo experiments.

Food and water were provided ad libitum. All treatment groups were age matched and randomized to treatment at the initiation of an experiment. The researchers performing the experiments were blinded to experimental groups during all testing. Animals were excluded from analysis if signs of fight with skin lesions were present.