Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Potential Orphan Drug Therapy of Intravesical Liposomal Onabotulinumtoxin-A for Ketamine-Induced Cystitis by Mucosal Protection and Anti-inflammation in a Rat Model.

Ketamine abusers may develop ulcerative cystitis and severe lower urinary tract symptoms, which is a medical dilemma. Recently, researchers have found the endemic of ketamine-induced cystitis worldwide. The intravesical administration of liposome-encapsulated onabotulinumtoxinA (Lipotoxin) might facilitate the healing of the damaged urothelium from liposomes, and reduce the urinary symptoms by onabotulinumtoxinA-induced chemo-denervation. Using female Sprague-Dawley rats, we investigated the effects of Lipotoxin on ketamine-induced cystitis. Functional magnetic resonance imaging, metabolic cage study, and cystometry were conducted. Paraffin-embedded sections were stained. The bladder mucosa and muscle proteins were assessed through Western blotting. We observed that repeated intravesical Lipotoxin instillation could improve suburothelial hemorrhage, recover the urothelial tight junction and adhesion proteins (zonula occludens-1 and E-cadherin), ensure less substance P in the urothelium, inhibit the overexpression of inflammatory mediators (IL-6, TNF-α, nuclear NF-κB, and COX-2) in the detrusor, suppress the upregulation of the mucosal TRPV1 and detrusor M2-mAChR, and ameliorate bladder overactivity in the ketamine-treated rats. These data reveal the mechanisms underlying the action of Lipotoxin in ketamine-induced cystitis of rats, which provide a basis of Lipotoxin for further treating ketamine-induced cystitis in humans.