MP07-07 INHIBITION OF TOLL-LIKE RECEPTOR 4 FOR TREATMENT OF CYSTITIS PAIN: A MAPP RESEARCH NETWORK STUDY

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis (MP07)1 Apr 2020MP07-07 INHIBITION OF TOLL-LIKE RECEPTOR 4 FOR TREATMENT OF CYSTITIS PAIN: A MAPP RESEARCH NETWORK STUDY Yi Luo*, Michael A. O'Donnell, Susan K. Lutgendorf, Catherine S. Bradley, Andrew Schrepf, Bradley A. Erickson, Vincent Magnotta, and Karl J. Kreder Yi Luo*Yi Luo* More articles by this author , Michael A. O'DonnellMichael A. O'Donnell More articles by this author , Susan K. LutgendorfSusan K. Lutgendorf More articles by this author , Catherine S. BradleyCatherine S. Bradley More articles by this author , Andrew SchrepfAndrew Schrepf More articles by this author , Bradley A. EricksonBradley A. Erickson More articles by this author , Vincent MagnottaVincent Magnotta More articles by this author , and Karl J. KrederKarl J. Kreder More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000827.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail 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. Source of Funding: NIH U01DK082344 and NIH R01DK111396 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e98-e98 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yi Luo* More articles by this author Michael A. O'Donnell More articles by this author Susan K. Lutgendorf More articles by this author Catherine S. Bradley More articles by this author Andrew Schrepf More articles by this author Bradley A. Erickson More articles by this author Vincent Magnotta More articles by this author Karl J. Kreder More articles by this author Expand All Advertisement PDF downloadLoading ...