Effect of intrathecal administration of E‐series prostaglandin 1 receptor antagonist in a cyclophosphamide‐induced cystitis rat model

Abstract

Abbreviations & Acronyms BOO = bladder outlet obstruction CMG = continuous cystometrogram CYP = cyclophosphamide DRG = dorsal root ganglia EDTA = ethylenediaminetetraacetate EP = E-series prostaglandin EP1 = E-series prostaglandin 1 GAPDH = glyceraldehyde-3-phosphate dehydrogenase IC = interstitial cystitis ICI = intercontraction interval i.t. = intrathecal NSB = non-specific binding OAB = overactive bladder PGE2 = prostaglandin E2 RT-PCR = reverse transcription polymerase chain reaction TA = total activity Objectives: To investigate the effect of intrathecal administration of E-series prostaglandin 1 antagonist in cyclophosphamide-induced murine cystitis. Methods: Female Wistar rats were used for this experimental study. Intrathecal administration of E-series prostaglandin 1 antagonist (ONO-8711; 0.5, 5 and 50 mg) in sham controls and rats with cystitis induced by a single intraperitoneal injection of cyclophosphamide (300 mg/kg) was assessed by evaluating micturition pressure and intercontraction interval using a conscious-filling cystometry at 48 h after cyclophosphamide or saline injection. In both groups, prostaglandin E2 concentrations and the expression of E-series prostaglandin 1 receptor in the spinal cord were measured by enzymelinked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Results: Rats with cyclophosphamide-induced cystitis showed a shorter intercontraction interval compared with controls, where the cumulative intrathecal administration of ONO-8711 did not significantly change micturition pressure or intercontraction interval compared with the baseline. In rats with cyclophosphamide-induced cystitis, each dose of ONO-8711 significantly increased the intercontraction interval compared with the baseline (46% increase at 50 mg intrathecally). Polymerase chain reaction revealed the expression of E-series prostaglandin 1 receptor in the spinal cord of both sham and cyclophosphamide-induced cystitis rats. In rats with cyclophosphamide-induced cystitis, PGE2 concentration in the dorsal horn of the L5-6 spinal cord was significantly higher than that in controls (3.55 Ϯ 1.24 vs 0.99 Ϯ 0.06 pg/mg tissue). Conclusions: In rats with cyclophosphamide-induced cystitis, urinary frequency seems to be caused by prostaglandin E2 acting on E-series prostaglandin 1 receptor at the level of the spinal cord. Blockade of the spinal E-series prostaglandin 1 receptor by ONO-8711 might have a therapeutic potential in the control of interstitial cystitis/bladder pain syndrome.

Functional and Molecular Characterization of Hyposensitive Underactive Bladder Tissue and Urine in Streptozotocin-Induced Diabetic Rat

“…Five ml of conjugate was added to TA well and 200 µL of Ellman's reagent was added to each well. PGE2 concentration was determinedd after absorbance measurement at 405 nm with a microplate reader (BIO-TEK, μQuant, USA) [24].…”

Modulation of afferent nerve activity by prostaglandin E2 upon urinary bladder distension in rats

“…The sensitivity of Aδ fibres suggests that they are potentially involved in PGE 2 -induced pathophysiological states, such as urinary frequency and urgency in OAB, as well as C fibres. It has been shown that the dorsal root ganglion neurons innervating the urinary bladder express mRNAs encoding PGE 2 receptors, including EP1 (Wada et al 2013) and EP3 (Su et al 2008), both of which are G protein-coupled E-series prostaglandin (EP) receptors. Blockade of the EP3 receptor specifically attenuated firing of fibres with a slower CV and a higher firing threshold (i.e.…”

Urodynamic effects of intravenous and intrathecal administration of E‐series prostaglandin 1 receptor antagonist on detrusor overactivity in rats with spinal cord injury

“…In rats with bladder outflow obstruction, intravenous administration of an EP1 antagonist showed an increase in micturition intervals and a decrease in NVCs . In cystitis model rats, the expression of spinal EP1 receptors was upregulated, and intrathecal administration of an EP1 receptor antagonist prolonged ICI . Thus, it is likely that EP1 receptors contribute to LUT dysfunction under pathological conditions.…”

“…Intravenous administration of an EP1 receptor antagonist increased micturition intervals and decreased non‐voiding contractions (NVC) in rats with bladder outlet obstruction . Our previous study using cystitis rats also demonstrated that intrathecal administration of an EP1 antagonist increased the micturition interval . Thus, we hypothesized that PGE2 and EP1 receptors would also be involved in bladder storage dysfunction after SCI.…”

“…7 Our previous study using cystitis rats also demonstrated that intrathecal administration of an EP1 antagonist increased the micturition interval. 8 Thus, we hypothesized that PGE2 and EP1 receptors would also be involved in bladder storage dysfunction after SCI. Therefore, we evaluated the urodynamic effects of an EP1 receptor antagonist in a SCI rat model to investigate the role of PGE2 and EP1 receptors in bladder activity after SCI.…”