Inhibition of NMDAR Reduces Bladder Hypertrophy and Improves Bladder Function in Cyclophosphamide Induced Cystitis

Abstract

Purpose We examined the role of NMDAR in the regulation of bladder hypertrophy and function in a rat model of cyclophosphamide induced cystitis. Materials and Methods Cystitis was induced by intraperitoneal injection of cyclophosphamide (150 mg/kg body weight). NMDAR phosphorylation (activity) and signal transduction pathways were examined by direct measurement and by specific inhibitors in vivo. Bladder hypertrophy was measured by bladder weight/body weight and type I collagen expression. Bladder function was examined by metabolic recording, conscious cystometry and detrusor muscle strip contractility in response to carbachol. Results NMDAR activity measured by the phosphorylation level of the NMDAR1 (NR1) subunit was expressed in the spinal cord but not in the bladder at 48 hours of cystitis. NMDAR inhibition with dizocilpine (MK-801) reduced the cystitis induced increment of bladder weight and type I collagen up-regulation in the bladder. NMDAR regulated type I collagen up-regulation was mediated by the PI3K/Akt pathway. NMDAR inhibition also attenuated cystitis induced urinary frequency measured by metabolic cage and cystometry. Cystitis decreased the responsiveness of detrusor muscle strips to carbachol, which was reversed by MK-801 in vivo. Unlike MK-801 the NMDAR antagonist D-AP5, which could not block central NMDAR activity, had no effect on bladder hypertrophy, type I collagen up-regulation or Akt activation caused by cystitis in the bladder. Conclusions Findings suggest that NMDAR activity has a role in cystitis induced bladder hypertrophy and overactivity. NMDAR mediated Akt activation may underlie the mechanism of bladder dysfunction.

Uroprotective mechanisms of natural products against cyclophosphamide-induced urinary bladder toxicity: A comprehensive review

“…A study of Al-Yahya and his colleagues reported that the responsiveness of the isolated urinary bladder rings from animals treated with CYP to Ach was markedly decreased when compared to the control group (Al-Yahya et al, 2009). During cystitis, type I collagen was upregulated and deposited leading to bladder wall thickness and this decreases the tension force of detrusor wall strips to stimuli (Liu et al, 2015).…”

Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice

“…Increased levels of oxidative stress promote oxidation and degradation of the sGC heme group, leading to an impairment of the NO-cGMP signaling pathway. Cystitis has been associated with decreased antioxidant mechanisms and accumulation of oxidative stress molecules (26,34). We hypothesized that activation of sGC by BAY 58-2667 prevents cyclophosphamide (CYP)-induced cystitis through the enhancement of sGC activity and cGMP levels, consequently improving bladder function.…”

Activation of the mTOR dependent signaling pathway underlies ketamine‐induced uropathy

“…Regarding the inflammatory reaction regulated by NMDAR1 in human brain endothelial cells, Reijerkerk et al proposed that NMDAR1 regulates monocyte transmigration through the brain endothelial cell barrier . Liu et al demonstrated that NMDAR1, expressed in the spinal cord of rats with cyclophosphamide‐induced cystitis, mediated type I collagen up‐regulation by activating the PI3K/Akt pathway . Consequently, we proposed a potential pathogenic mechanism of KC in which activation of NMDAR1 in endothelial cells induces another type of cellular transition, EndMT, emerging as a crucial mode of pathogenesis in tissue fibrosis …”