Abstract
BackgroundOnabotulinumtoxin A (OnabotA) injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia. An OnabotA - induced volume reduction caused by sympathetic fibers impairment has been proposed as a potential mechanism of action. Our aim was to investigate the expression of apoptosis-regulating proteins in the rat prostate following OnabotA intraprostatic injection.MethodsAdult Wistar rats were injected in the ventral lobes of the prostate with 10 U of OnabotA or saline. A set of OnabotA-injected animals was further treated with 0.5 mg/kg of phenylephrine (PHE) subcutaneously daily. All animals were sacrificed after 1 week and had their prostates harvested. Immunohistochemical staining was performed for Bax, Bcl-xL and caspase-3 proteins and visualized by the avidin-biotin method. The optical density of the glandular cells was also determined, with measurement of differences between average optical densities for each group.ResultsSaline-treated animals showed intense epithelial staining for Bcl-xL and a faint labelling for both Bax and Caspase-3. OnabotA-treated rats showed a reduced epithelial staining of Bcl-xL and a consistently increased Bax and Caspase-3 staining when compared with saline-treated animals. PHE-treated animals showed a stronger Bcl-xL staining and reduced staining of both Bax and Caspase-3 when compared to the OnabotA group. Mean signal intensity measurements for each immunoreaction confirmed a significant decrease of the signal intensity for Bcl-xL and a significant increase of the signal intensity for Bax and Caspase 3 in OnabotA-injected animals when compared with the control group. In OnabotA+PHE treated animals mean signal intensity for Bcl-xL, Bax and Caspase 3 immunoreactions was identical to that of the control animals.ConclusionsThese results support the hypothesis that OnabotA activates apoptotic pathways in the rat prostate through a mechanism that involves sympathetic outflow impairment.
Highlights
Onabotulinumtoxin A (OnabotA) injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia
A 30 to 50% reduction in prostate volume was observed in several human trials in which Botulinum toxin type A (BoNT/A) was injected in moderate-to-large volume glands [4,5], in a large phase 2 clinical trial, neither the prostate volume nor the serum PSA showed any significant decrease following the neurotoxin injection [6]
Mean signal intensity measurements for each immunoreaction confirmed a significant decrease of the signal intensity for Bcl-xL and a significant increase of the signal intensity of Caspase 3 and Bax immunoreactions in OnabotA-injected animals when compared with control groups
Summary
Onabotulinumtoxin A (OnabotA) injection has been investigated as a novel treatment for benign prostatic enlargement caused by benign prostatic hyperplasia. Our aim was to investigate the expression of apoptosis-regulating proteins in the rat prostate following OnabotA intraprostatic injection. It has been repeatedly demonstrated that BoNT/A induces apoptosis in rat and dog prostates, as shown by a positive deoxynucleotidyl transferase biotindUTP nick-end labelling (TUNEL) [2,3,7,8]. Subcutaneous injection of the sympathicomimetic agent phenylephrine (PHE) in BoNT/A-injected rats seems to attenuate the TUNEL reaction [8], suggesting that the sympathetic nervous system could play an important role in the mechanisms of cell survival in the prostate gland, as previously forwarded by McVary and colleagues [10]
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