Abstract
MP07-07 INHIBITION OF TOLL-LIKE RECEPTOR 4 FOR TREATMENT OF CYSTITIS PAIN: A MAPP RESEARCH NETWORK STUDY
The Journal of urology, Vol.203(Supplement 4), pp.e98-e98
04/2020
DOI: 10.1097/JU.0000000000000827.07
Abstract
INTRODUCTION AND OBJECTIVE:
Our prior clinical studies indicated a link between altered Toll-like receptor (TLR) 4 activation and pain in interstitial cystitis/bladder pain syndrome (IC/BPS). Consistently, we recently observed altered TLR4 activation in our developed IC/BPS-like transgenic autoimmune cystitis murine model (URO-OVA), which was associated with pelvic/bladder pain seen in IC/BPS patients. The objective of this study was to determine whether inhibition of TLR4 could result in pelvic/bladder pain relief in our validated IC/BPS-like URO-OVA model.
METHODS:
URO-OVA mice develop bladder inflammation and associated pelvic/bladder pain with a peak at 7-14 days after cystitis induction. At day 7 after cystitis induction, mice (female, 8 weeks old) were treated intravenously (i.v.) with vehicle (n=10) or TAK-242, a well-defined small inhibitory compound selective for TLR4, at 2.5 mg/kg (n=10). At one-hour posttreatment, mice were evaluated for pelvic pain by von Frey filament stimulation and bladder pain by bladder distention-evoked visceromotor response, respectively. Normal mice (n=10) were included for comparison. To evaluate systemic TLR4 activation, splenocytes were prepared and stimulated with lipopolysaccharide (LPS), a TLR4 agonist, at tenfold escalating doses ranging from 10-5 to 102 µg/ml for 24 hours, followed by ELISA analysis of proinflammatory cytokine (IL-1β, IL-6 and TNF-α) production in vitro. To evaluate central TLR4 activation, lumbar spinal cords were collected and processed for total RNA extraction, followed by RT-PCR analysis of ex vivo levels of mRNAs for proinflammatory cytokines IL-6 and TNF-α as well as endogenous TLR4 ligand high mobility group box-1 (HMGB1).
RESULTS:
URO-OVA mice developed pelvic/bladder pain, along with altered systemic and central TLR4 activations, after cystitis induction. Compared to vehicle-treated mice, TAK-242-treated mice showed significantly (∼90%) reduced pelvic/bladder pain. This reduced pain was associated with significantly reduced splenocyte production of TLR4-mediated proinflammatory cytokines (at 10 µg/ml of LPS: 36% reduction for IL-1β, 43% reduction for IL-6, and 57% reduction for TNF-α) and substantially reduced spinal cord expression of mRNAs for IL-6, TNF-α and HMGB1.
CONCLUSIONS:
TAK-242 effectively attenuates pelvic/bladder pain in cystitis through inhibition of altered systemic and central TLR4 activations in the URO-OVA model, providing a potentially useful therapeutic agent for the treatment of IC/BPS pain in humans.
Details
- Title: Subtitle
- MP07-07 INHIBITION OF TOLL-LIKE RECEPTOR 4 FOR TREATMENT OF CYSTITIS PAIN: A MAPP RESEARCH NETWORK STUDY
- Creators
- Yi LuoMichael A O'DonnellSusan K LutgendorfCatherine S BradleyAndrew SchrepfBradley A EricksonVincent MagnottaKarl J Kreder
- Resource Type
- Abstract
- Publication Details
- The Journal of urology, Vol.203(Supplement 4), pp.e98-e98
- DOI
- 10.1097/JU.0000000000000827.07
- ISSN
- 0022-5347
- eISSN
- 1527-3792
- Grant note
- NIH U01DK082344 and NIH R01DK111396
- Language
- English
- Date published
- 04/2020
- Academic Unit
- Epidemiology; Psychological and Brain Sciences; Psychiatry; Roy J. Carver Department of Biomedical Engineering; Obstetrics and Gynecology; Radiology; Urology; Iowa Neuroscience Institute
- Record Identifier
- 9984065775702771
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