Abstract
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.
Highlights
Ketamine-induced cystitis (KIC) is characterized by its interstitial cystitis-like symptoms among ketamine abusers, namely a painful bladder, dysuria, urgency, urinary frequency, and hematuria[1]
No significant difference was observed between the ketamine/Lipotoxin and control groups in the MRI signals in the periaqueductal grey (PAG) area, micturition frequency, and intercontractile intervals
The ketamine/Lipotoxin group had insignificant changes from controls, except for IL-1β and M3-muscarinic acetylcholine receptors (mAChRs) overexpression in the detrusor. These results demonstrate that repeated Lipotoxin instillation may have the potential in treating KIC by ameliorating bladder overactivity, ensuring mucosal protection, inhibiting detrusor inflammation, modulating the aberrant vesical neurotransmission, and inhibiting central sensitization
Summary
Ketamine-induced cystitis (KIC) is characterized by its interstitial cystitis-like symptoms among ketamine abusers, namely a painful bladder, dysuria, urgency, urinary frequency, and hematuria[1]. Researchers have established animal models of KIC8–10 to understand its pathophysiology and develop novel treatments They reported that urothelial barrier dysfunction, neurogenic inflammation, and aberrant bladder neurotransmission are the main pathologies of KIC. BoNT-A inhibits vesicular neurotransmitter release at the neuromuscular and neuroglandular junctions by cleaving the synaptosomal-associated protein, 25 kDa (SNAP25) responsible for the exocytosis of synaptic vesicles[15] Through this mechanism of action, BoNT-A can cause motor effects on partial paralysis of detrusor and sensory effects on inhibition of afferent neurotransmission by blocking release of sensory neurotransmitters, such as substance P and calcitonin gene-related peptide. The potential activity sites for the intravesical instillation of Lipotoxin include the urothelium and vesical afferent and efferent signal pathways[11] In this translational study, we investigate the potential of intravesical Lipotoxin instillation for treating KIC in a rat model[9]. The alterations of micturition behavior, urothelial injuries, and inflammatory mediators and neuroreceptors of the bladder were evaluated
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