Blocking mammalian target of rapamycin alleviates bladder hyperactivity and pain in rats with cystitis

Abstract

BackgroundBladder disorders associated with interstitial cystitis are frequently characterized by increased contractility and pain. The purposes of this study were to examine (1) the effects of blocking mammalian target of rapamycin (mTOR) on the exaggerated bladder activity and pain evoked by cystitis and (2) the underlying mechanisms responsible for the role of mTOR in regulating cystic sensory activity.ResultsThe expression of p-mTOR, mTOR-mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4 E–binding protein 4 (p-4 E-BP1), as well as phosphatidylinositide 3-kinase (p-PI3K) pathway were amplified in cyclophosphamide rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated bladder hyperactivity and pain. In addition, blocking PI3K signal pathway attenuated activities of mTOR, which was accompanied with decreasing bladder hyperactivity and pain. Inhibition of either mTOR or PI3K blunted the enhanced spinal substance P and calcitonin gene-related peptide in cyclophosphamide rats.ConclusionsThe data for the first time revealed specific signaling pathways leading to cyclophosphamide-induced bladder hyperactivity and pain, including the activation of mTOR and PI3K. Inhibition of these pathways alleviates cystic pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of overactive bladder and pain often observed in cystitis.

Blocking PAR2 alleviates bladder pain and hyperactivity via TRPA1 signal

“…Numerous receptors present on the presynaptic site of the nerve terminals contribute to the release of substance P and CGRP, thus regulating inflammatory pain [11]. Specifically, our recent study suggests that substance P and CGRP in the dorsal horn are engaged in CYP-induced bladder mechanical hyperalgesia [26]. Inhibition of the PAR2 signal pathway can affect the levels of substance P and CGRP in the dorsal horn and alter the process of pain responses.…”

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

“…In our studies, the reduction in kinase expression with imatinib was most prominent with pAKT and in the D. LP. A major downstream target of pAKT is mTOR (Manning and Toker, 2017) which may contribute to IC/BPS (Yang et al, 2012;Lin et al, 2015;Liang et al, 2016;Xie et al, 2018;Liu et al, 2020). Intrathecal blockade of the PI3K/AKT-mTOR pathway reduced bladder hyperactivity, somatic sensitivity, and spinal cord substance P and CGRP protein expression in female rats with chronic CYPinduced cystitis (Liang et al, 2016).…”

“…Cytokines, chemokines, growth factors and their related receptors, including PDGFRα, may activate cell signaling pathways such as the MAPK/ERK and PI3K/AKT pathway, which can lead to transcriptional and translational changes promoting cell survival, growth, inflammation, and proliferation (Heldin and Westermark, 1999;Andrae et al, 2008). Increased expression of phosphorylated (p) ERK and pAKT have been reported in the urinary bladder, and lumbosacral DRG and spinal cord of rodents with CYP-induced cystitis, and blockade improves LUT functional outcomes (Cruz et al, 2005;Vizzard, 2007, 2009;Qiao and Gulick, 2007;Chung et al, 2010;Arms and Vizzard, 2011;Yu et al, 2012;Coelho et al, 2014;Qiao et al, 2014;Liu et al, 2015;Liang et al, 2016).…”

Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes

“…A small molecule SHIP1 allosteric regulator (AQX-1125/Rosiptor) ( Stenton et al., 2013a , 2013b ) developed independently of the authors of this manuscript was recently tested in clinical trials for relief of urinary bladder pain experienced by interstitial cystitis (IC) patients ( Nickel et al., 2016 ). IC reportedly was chosen for the disease indication because AQX-1125/Rosiptor accumulates in the urinary bladder ( Stenton et al., 2013b ), two papers implicated PI3K-dependent inflammation in IC ( Liang et al, 2016 ; Qiao et al., 2014 ), and preliminary phase 2 trials seemed promising ( Nickel et al., 2016 ). However, the phase 3 trial failed to show efficacy for AQX-1125/Rosiptor ( Nickel et al., 2019 ).…”