**5. Inhibition of Chronic Inflammation and Hypersensitivity by Intravesical Botulinum Toxin A Injection**

Injection of botulinum toxin A (BoNT-A) into the detrusor muscle has emerged as a successful treatment for idiopathic and neurogenic detrusor overactivity [35,36]. Figure 1 summarizes some possible mechanisms that have been proposed to support its clinical efficacy for patients with DM-associated OAB [37]. Firstly, BoNT-A is well known for its ability to block the neuronal release of acetylcholine at the neuromuscular junction and therefore to inhibit abnormal smooth muscle contractions. Secondly, BoNT-A not only inhibits the efferent pathway of the bladder but also suppresses hypersensitivity via the afferent pathway. Thirdly, BoNT-A has anti-inflammatory effects and blocks noxious neurotransmitter release from the urothelium, including substance P, calcitonin gene-related peptide, and adenosine triphosphate (ATP). Finally, BoNT-A could be transported both anterogradely and retrogradely along either motor or sensory axons for bi-directional delivery between peripheral tissues or the central nerve system. Significant accumulation of the radio-labeled BoNT-A was noted in the lumbosacral dorsal root ganglia after bladder injection in normal rats [38,39]. Thus, BoNT-A might block not only acetylcholine release from motor nerve terminals but also central synaptic transmission, including glutamate, noradrenaline, dopamine, ATP, gamma-aminobutyric acid, and glycine. Since the pathophysiology of DM-associated OAB consists of afferent and efferent neuropathy, chronic inflammation and urothelial dysfunction, intravesical BoNT-A injection might be effective to treat DM-associated OAB.

**Figure 1.** The early effect of diabetes mellitus on the innervation or function of the neuronal component, detrusor smooth muscle, and urothelium. Pentagram sign implies the possible mechanism of BoNT-A to support the clinical efficacy for DM-associated overactive bladder (OAB). The arrow means "increase".

Several experimental studies could support the clinical use of BoNT-A in treatment of DM-associated OAB. In acute and chronic inflammation in a rat model, BoNT-A significantly inhibited the release of substance P and calcitonin gene-related peptide after acute and chronic bladder injury [40]. In spinal-cord-injured rats, BoNT-A reversed the ratio of excitatory (ATP) and inhibitory (nitric oxide) urothelial transmitters and decreased non-voiding bladder contraction frequency [41]. In BOO-induced detrusor overactivity in rats, the expressions of nerve growth factor and transient receptor potential vanilloid 1 (TRPV1) proteins in the urothelium were significantly higher in the BOO group than in the control group and the expressions decreased significantly with BoNT-A detrusor injections [42]. In children with neurogenic detrusor overactivity, BoNT-A detrusor injections led to significant reductions in muscarinic M2, M3, P2X2, and purinergic P2X1, P2X2, and P2X3 receptors [43]. In another neurogenic bladder study in 15 children with myelodysplasia, urinary transforming growth factor beta-1 and nerve growth factor declined following intradetrusor BoNT-A injection [44]. These animal and clinical studies of BoNT-A strengthen the evidence of its therapeutic effects in diabetic patients with OAB. Since muscarinic M3 and P2X3 protein expressions in the bladders of DM-associated OAB patients were significantly higher than those in the controls, BoNT-A detrusor injection may provide an alternative treatment for these patients [23].
