Imatinib Mesylate Reduces Neurotrophic Factors and pERK and pAKT Expression in Urinary Bladder of Female Mice With Cyclophosphamide-Induced Cystitis

Abstract

Imatinib mesylate is a tyrosine kinase inhibitor that inhibits platelet-derived growth factor receptor (PDGFR)-α, -β, stem cell factor receptor (c-KIT), and BCR-ABL. PDGFRα is expressed in a subset of interstitial cells in the lamina propria (LP) and detrusor muscle of the urinary bladder. PDGFRα + interstitial cells may contribute to bladder dysfunction conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) or overactive bladder (OAB). We have previously demonstrated that imatinib prevention via oral gavage or treatment via intravesical infusion improves urinary bladder function in mice with acute (4 hour, h) cyclophosphamide (CYP)-induced cystitis. Here, we investigate potential underlying mechanisms mediating the bladder functional improvement by imatinib using a prevention or treatment experimental design. Using qRT-PCR and ELISAs, we examined inflammatory mediators (NGF, VEGF, BDNF, CCL2, IL-6) previously shown to affect bladder function in CYP-induced cystitis. We also examined the distribution of phosphorylated (p) ERK and pAKT expression in the LP with immunohistochemistry. Imatinib prevention significantly (0.0001 ≤ p ≤ 0.05) reduced expression for all mediators examined except NGF, whereas imatinib treatment was without effect. Imatinib prevention and treatment significantly (0.0001 ≤ p ≤ 0.05) reduced pERK and pAKT expression in the upper LP (U. LP) and deeper LP (D. LP) in female mice with 4 h CYP-induced cystitis. Although we have previously demonstrated that imatinib prevention or treatment improves bladder function in mice with cystitis, the current studies suggest that reductions in inflammatory mediators contribute to prevention benefits of imatinib but not the treatment benefits of imatinib. Differential effects of imatinib prevention or treatment on inflammatory mediators may be influenced by the route and frequency of imatinib administration and may also suggest other mechanisms (e.g., changes in transepithelial resistance of the urothelium) through which imatinib may affect urinary bladder function following CYP-induced cystitis.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis

“…A recent preclinical study reported that blockade of VEGF/VEGFR-2 signaling in rat model of acute and chronic cyclophosphamide (CYP)-induced cystitis resulted in increased bladder capacity and voided volume 18 . Similarly, imatinib, a tyrosine kinase inhibitor that inhibits PDGFR-A, -B, and C-kit, alleviated the altered expression of such receptors in rat bladders with CYP-induced cystitis 19 .…”

Stress-induced symptom exacerbation: Stress increases voiding frequency, somatic sensitivity, and urinary bladder inflammation when combined with low concentration cyclophosphamide treatment in mice

“…Serum was aliquoted and frozen at −20 °C until analysis. We determined NGF and BDNF, IL-6 and CXC (CXCL9, CXCL10) protein content in the urinary bladder of control, CYP, RVS and CYP+RVS treatment groups (N=8) using ELISAs (Promega, Madison, WI and R&D Systems, Minneapolis, MN) as previously described (18,19,31,32,48). According to the manufacturer, the NGF E-max or BDNF E-max immunoassay systems (Promega, Madison, WI) demonstrate very low cross-reactivity with structurally related growth factors.…”

“…In this paper, we describe our characterization of the SISE model including, bladder function with conscious, open outlet continuous cystometry and somatic sensitivity with von Frey filament testing. We have also examined corticosterone expression, and expression of inflammatory mediators including neurotrophic factor (NGF, BDNF) (18)(19)(20), chemokine (CXC) and interleukin-6 (IL-6) (18,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) expression in the urinary bladder. These initial results demonstrated that CYP alone, or RVS alone creates a change in the inflammatory environment of the urinary bladder and a systemic increase in corticosterone expression but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS).…”