From Lab to ClinicEffects of Botulinum Toxin A on the Contractile Function of Dog Prostate
Introduction
Although prostatectomy is effective in treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), its potential complications preclude acceptance by many patients. Less invasive therapy, like botulinum toxin A (BoNT/A) injection, is therefore desirable. BoNT/A inhibits cleavage of the cytosolic translocation protein synaptosomal-associated membrane protein (SNAP-25) and prevents fusion of neurotransmitter-containing vesicles with plasma membrane, resulting in inhibited release of neurotransmitters. BoNT/A inhibited acetylcholine release from presynaptic nerve terminals, which resulted in decreasing muscle tone in skeletal and smooth muscles. BoNT/A has been used to reduce spasticity of skeletal muscles, improve symptoms of strabismus [1], and reduce facial wrinkles [2]. Recent papers also demonstrated the therapeutic effects of intravesical injection of BoNT/A for detrusor overactivity [3], [4].
Growth and secretion of some exocrine glands, including sweat glands and salivary glands, are also modulated by cholinergic nerves, which are subjected to blockade by BoNT/A. Clinical studies showed that BoNT/A injection might decrease sweating and improved symptoms of hyperhydrosis [5], [6]. Several papers have already reported good results in treating sialorrhoea by BoNT/A injection into salivary glands [7], [8].
Studies have indicated that the prostatic gland is richly innervated by cholinergic nerves [9], [10]. Theoretically, prostatic glandular secretion should also be depressed by BoNT/A. One study did show atrophic effects of BoNT/A on rat prostate. One and 2 wk after prostate BoNT/A injection, a significant atrophy of prostate glands was found, with an abundance of apoptosis [11]. Kuo [12] and also Chuang et al [13] demonstrated that BoNT/A was effective in reducing prostate size and symptoms of BPH. These laboratory and clinical studies clearly show that BoNT/A could induce an atrophic change in the prostate gland. Nevertheless, the effect of BoNT/A on prostate contractile function is still unknown.
Contractile function of the prostate comes from smooth muscle cells in the stroma component, which are adrenergically innervated [14]. Upon stimulation with alpha-adrenergic agonists, smooth muscle fibers of the prostate contract, resulting in increased bladder outlet resistance. This dynamic occlusive force may account for 40% of obstruction caused by BPH [15], suggesting that contractile function of the prostate plays an important role in pathophysiology of bladder outlet obstruction secondary to BPH. In this study, we used an animal model to research effects of BoNT/A on prostrate contractile function.
Section snippets
Animals
Mature male mongrel dogs, body weight 10–15 kg, were used in this study. The study was approved by the Institutional Review Board (IRB) for Animal Research in our institution.
In vivo prostate urethral pressure response to intravenous norepinephrine
We have used this method previously, and it has been described in our published paper [16]. An 8F catheter specifically designed for measuring urethral closure pressure (Life-tech, Texas, USA) was inserted into the bladder through the urethra. Through a three-way stopcock, the catheter was connected to an infusion pump (1.4
Effects of BoNT/A on prostate urethral pressure response to IV norepinephrine
Before injection, there were no statistically significant differences in the size of the prostate between the groups with 24.0 ± 4.5, 22.3 ± 3.4, and 28.1 ± 4.1 ml for control, 100U, and 200U group, respectively. One month after injection there was no significant change in the prostate size in control and 100U groups. The size of the prostate in 200U group had a mean of 24% reduction.
Before injection, there was no statistically significant difference in basal prostate urethral pressure between the
Discussion
The present study confirms that BoNT/A induces atrophy of glandular component of dog prostate as shown by Chuang el at [17]. The present study further demonstrated that, with an adequate dose, BoNT/A also reduced contractile activity of the prostate. In vivo and in vitro contractile responses of the prostate to stimulations were reduced by injecting 200 units BoNT/A. The impaired contractility may come from two factors: (1) impaired release of contractile neurotransmitters; (2) impaired
Conclusions
The present study confirms that BoNT/A may induce atrophy of the prostate gland and reduce contractile activity of prostate tissue in dogs. These properties make BoNT/A a viable option in managing prostate-related LUTS. However, large, randomized clinical studies to determine long-term effects and safety of BoNT/A application in human prostates are required.
Conflicts of interest
The authors have nothing to disclose.
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2019, Progres en UrologieBotulinum toxin and benign prostatic hyperplasia
2018, Asian Journal of UrologyCitation Excerpt :With the blockade of release in acetylcholine, marked atrophy and diffused apoptosis is found in canine models treated with BoNT-A [4]. Other studies on the dynamic contractions of canine prostates injected with BoNT-A 100 U, 200 U and control with saline showed significantly less contraction on electrostimulation and intravenous norepinephrine in the 200 U group compared with 100 U or saline group [5]. Hence it can be deduced that effect of BoNT works on both the structural as well as dynamic component of BPH.
Botulinum Neurotoxin and Its Potential Role in the Treatment of Erectile Dysfunction
2018, Sexual Medicine ReviewsCitation Excerpt :BoNT has been used for prostatic smooth muscle relaxation in the management of lower urinary tract symptoms.14 It also has been found to inhibit noradrenaline release in the urethra and anococcygeus of rats15,16 and prostatic tissue of dogs.17 The duration of effect of BoNT-A in striated muscle is roughly 2 to 3 months; however, in smooth muscle, its effects are believed to last longer.11
Botulinum toxin A treatment for lower urinary tract symptoms/benign prostatic hyperplasia
2017, Urological ScienceGuidelines for the management of benign prostatic hyperplasia. Colombian Urological Society 2014
2015, Urologia ColombianaMechanism of action of onabotulinumtoxinA on lower urinary tract dysfunction
2014, Tzu Chi Medical JournalCitation Excerpt :BoNT-induced prostatic gland atrophy, and in some cases apoptosis, was identified in rats as well as in dogs [28,30]. In addition, Lin et al [31] reported that an injection of 200 U onabotulinumtoxinA into the canine prostate significantly reduced the prostate urethral pressure response to intravenous norepinephrine and electrostimulation. They concluded that BoNT reduces the contractile function of the prostate and may attenuate the dynamic component of BPH.