Clinical significance of interleukin‑6 and inducible nitric oxide synthase in ketamine‑induced cystitis

Abstract

Ketamine is an ionotropic glutamatergic N-methyl-D-aspartate receptor antagonist, which is widely used among recreational drug abusers. Ketamine abusers exhibit substantially reduced bladder capacity, which can lead to urinary frequency. The molecular pathogenesis of ketamine-induced cystitis has been scarcely reported. Given previous clinical findings, it may be hypothesized that pathological alterations in smooth muscle cells (SMCs) of the urinary bladder serve a crucial role in the mechanism underlying cystitis. In the present study, two lineages of SMCs, one from differentiated foreskin-derived fibroblast-like stromal cells and the other from cultured normal aortic SMCs, were used to study ketamine-induced molecular alterations. Polymerase chain reaction was used to study the effects of ketamine on oxidative stress. The effects of adjuvant chemo-therapy with cyclophosphamide (CTX) were also investigated. The results indicated that the expression levels of interleukin-6 and inducible nitric oxide synthase (iNOS) were decreased, whereas collagen expression and deposition were increased in ketamine-treated SMCs. Conversely, treatment with CTX restored the expression of iNOS, which may prevent or limit oxidative damage. In conclusion, the present study demonstrated that ketamine may induce several molecular alterations in SMCs and these changes may be associated with the clinical symptoms observed in ketamine abusers. In addition, the specific chemotherapeutic agent CTX may reverse these ketamine-induced aberrations.

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis

“…In cultured smooth muscle cells (SMCs), ketamine induces dose‐dependent inhibitory effects on cell generation 19,20,224 . Among the MAPK family, ERK1/2 is one of the well‐known signal transduction pathways for SMC differentiation and proliferation.…”

“…In cultured smooth muscle cells (SMCs), ketamine induces dose-dependent inhibitory effects on cell generation. 19,20,224 Among the MAPK family, ERK1/2 is one of the well-known signal transduction pathways for SMC differentiation and proliferation. Besides, Akt, a serine/threonine protein kinase, was found to be activated via the PI3K pathway; it also plays roles in SMC differentiation and proliferation.…”

“…However, recent studies have made great advances in the pathogenesis of KC and demonstrated that the nerves, microvasculature, and bladder smooth muscle (BSM) in the bladders of patients with KC have pathological changes and display injuries. These ketamine‐induced tissue injuries involve various signaling pathways and contribute to the pathogenesis of KC 17‐20 . This review summarizes the molecular signaling pathways underlying these tissue injuries in the bladder of KC, to enhance the understanding of the pathophysiology of this disease and to facilitate the identification of novel pharmacologic targets for KC.…”

What urologists need to know about ketamine‐induced uropathy: A systematic review

“…Inflammation is confirmed by positive immunohistochemical staining for inflammatory markers (cyclooxygenase‐2, inducible nitric oxide synthase, matrix metallopeptidase‐9, mammalian target of rapamycin, and phosphorylated 40S ribosomal protein S6) 19,24 . Inducible nitric oxide synthase is responsible for the inflammation process because it is related to many cytokines, prostacyclin, prostaglandin E2, and cyclooxygenase pathways, which have severe inflammatory action and increase collagen expression and deposition 25,26 . Ketamine treatment in rats induces direct activation of the cyclooxygenase pathway with prostaglandin‐E2 production and an upregulation of cyclooxygenase‐2 expression in the bladder 27,28 .…”

Could Mesna and Celery Seed Cotherapy Modulate Oxidative Stress and Inflammation of the Urinary Bladder Induced by Ifosfamide in Rabbits?

“…Therefore, the complications of HC include hemorrhage, necrosis, fibrosis, and contracture of the urinary bladder (UB). 3 The pathogenesis of IFS-induced HC involves direct contact of acrolein with the urothelium, which induces inflammation of the UB. The urothelium is a simple barrier between urine and the UB that gets tremendous importance due to its prominent role in the pathophysiology of UB dysfunction.…”