Modulation of Urinary Bladder Innervation: TRPV1 and Botulinum Toxin A

Abstract

The persisting interest around neurotoxins such as vanilloids and botulinum toxin (BoNT) derives from their marked effect on detrusor overactivity refractory to conventional antimuscarinic treatments. In addition, both are administered by intravesical route. This offers three potential advantages. First, intravesical therapy is an easy way to provide high concentrations of pharmacological agents in the bladder tissue without causing unsuitable levels in other organs. Second, drugs effective on the bladder, but inappropriate for systemic administration, can be safely used as it is the case of vanilloids and BoNT. Third, the effects of one single treatment might be extremely longlasting, contributing to render these therapies highly attractive to patients despite the fact that the reasons to the prolonged effect are still incompletely understood. Attractive as it may be, intravesical pharmacological therapy should still be considered as a second-line treatment in patients refractory to conventional oral antimuscarinic therapy or who do not tolerate its systemic side effects. However, the increasing off-label use of these neurotoxins justifies a reappraisal of their pharmacological properties.

Botulinum Neurotoxin Serotype A Suppresses Neurotransmitter Release from Afferent as Well as Efferent Nerves in the Urinary Bladder

“…These data provide further support for the view that the urothelium has “neuronal-like” properties and may participate in bladder sensory mechanisms by releasing chemicals that modulate afferent nerve excitability [10]. However, another laboratory failed to detect SNAP-25 staining in human and rodent urothelium [11]. …”

Targets for botulinum toxin in the lower urinary tract

“…Attachment proteins, or soluble N ‐ethylmaleimide‐sensitive fusion attachment protein receptors (SNAREs), include synaptosome‐associated protein 25 kDa (SNAP‐25), vesicle‐associated membrane protein (VAMP)/synaptobrevin, and syntaxin. BoNT/A cleaves SNAP‐25 in contrast with subtype B, which acts preferentially on VAMP …”

“…BoNT/A also influences the expression of muscarinic and purinergic receptor subtypes present in the detrusor, urothelium, and suburothelium . The modification of the M3 receptor may be particularly relevant, as it mediates cholinergic‐mediated detrusor contractions as well as bladder afferent activity conveyed in both C and Aδ fibers . Changes in purinergic receptors may also be relevant.…”

“…BoNT/A is synthesized as a single polypeptide chain (≈150 kDa) which is cleaved into a light chain (≈50 kDa) and a heavy chain (≈100 kDa) held together by a fragile disulphide bond and noncovalent bonds. This structure subsequently forms a complex with other proteins, which provides additional characteristics, including resistance to proteolysis and denaturation . As the BoNT/A gene may differ in nucleotide sequence, four A subtypes have been classified based on up to 15% variation in the amino acid composition …”

“…The H CC is associated both with the recognition of neuronal‐specific areas and toxin internalization. The H N is responsible for translocation of the light chain from synaptic vesicles into the neuronal cytoplasm …”