Translational Aspects of Nuclear Factor-Kappa B and Its Modulation by Thalidomide on Early and Late Radiation Sequelae in Urinary Bladder Dysfunction

Abstract

This preclinical study aimed to investigate the role of nuclear factor (NF)-kB in early and late radiogenic sequelae of urinary bladder dysfunction in mice. Thalidomide was applied either during the early or late response phase to determine potential effects of NF-kB inhibition on functional bladder impairment. Methods and Materials: After pelvic irradiation on day 0, female C3H/Neu mice were observed over a period of 360 days and radiation response was evaluated for alterations in bladder functionality and NF-kB activation. Functionality was determined in graded dose experiments (14-24 Gy) and assessed by micturition frequency analysis and transurethral cystotonometry to reveal alterations in voiding and volume. The induction of the NF-kB proteins p50 and p65 was evaluated by immunohistochemistry in response to a single dose of 23 Gy (ED 90). Thalidomide (100 mg/kg/d) was applied intraperitoneally in 3 treatment groups: daily from day 1 to 15, daily from day 16 to 30, and in 2-day-intervals from day 150 to 180. Results: Immunohistochemical analysis showed a biphasic activation of p50 and p65 during the early radiation cystitis phase (day 1-30). After a transient decrease, p50, but not p65, was reactivated permanently leading to increased levels, which suggests an occurrence of chronic inflammation correlated with functional impairment. Both early thalidomide treatments reduced NF-kB activation and shifted the ED 50 value for early radiation cystitis and late radiation sequelae to higher doses. Conclusions: These data clearly demonstrate the involvement of NF-kB signaling in the pathogenesis of radiation-induced urinary bladder dysfunction. Additionally, this study emphasizes that biological targeting of early radiogenic processes has enormous effect on chronic symptoms. The late administration of thalidomide showed no significant effect on functionality.

Effect of irradiation on the expression of E-cadherin and β-catenin in early and late radiation sequelae of the urinary bladder and its modulation by NF-κB inhibitor thalidomide

“…P50 homodimers are associated with the upregulation of driving factors for chronic inflammation [17,28,[44][45][46][47][48]. Thalidomide treatment during this late phase (THA150-180) achieved no relevant treatment effect in our previous functional study and it seems that thalidomide has no long-lasting effects on chronic NF-κB activation [17]. Thalidomide treatment during the late phase (THA150-180) had also no significant effect on E-cad-herin expression and only minor effects on β-catenin with an earlier rise on day 180 and a higher expression on day 300 than in the irradiated control.…”

“…A total of 915 mice were assigned to the following five groups ( or in two-day intervals from day 150 to 180 in treatment group THA150-180 (126 samples) [17].…”

“…Present treatment methods for ERC did not show any ameliorating effects on LRS, but current research data suggested that the nuclear factor-kappa B (NF-κB) pathway is involved in the inflammatory processes [ 17 ]. Functional studies in the same mouse model as in the current study assessed the time course of ERC and LRS by transurethral cystotonometry and immunohistochemical analyses and showed a biphasic activation of the NF-κB proteins p50 and p65 during ERC and p50 reactivation in the late phase [ 17 ]. Furthermore, the systemic administration of the NF-κB inhibitor thalidomide during the early phase had promising beneficial effects on ERC and the incidence and severity of the LRS [ 17 ].…”

“…Functional studies in the same mouse model as in the current study assessed the time course of ERC and LRS by transurethral cystotonometry and immunohistochemical analyses and showed a biphasic activation of the NF-κB proteins p50 and p65 during ERC and p50 reactivation in the late phase [ 17 ]. Furthermore, the systemic administration of the NF-κB inhibitor thalidomide during the early phase had promising beneficial effects on ERC and the incidence and severity of the LRS [ 17 ]. It reduced NF-κB activation and shifted the ED50 value for early radiation cystitis and late radiation sequelae to higher doses [ 17 ].…”

Chronic Inflammation and Radiation-Induced Cystitis: Molecular Background and Therapeutic Perspectives

“…Considering the immunomodulatory effect of thalidomide, Kowaliuk et al recently investigated the role of NF-κB and the functional effects of this treatment on radiogenic bladder dysfunction. Early thalidomide infusion after pelvic irradiation using a YXLON MG325 X-ray device showed beneficial and promising effects on the incidence and severity of bladder dysfunction [ 79 ]. The late administration of thalidomide showed no significant effect on functionality with possible neurological side effects, limiting its use [ 80 ].…”