title: l-Theanine inhibits proinflammatory PKC/ERK/ICAM-1/IL-33 signaling, apoptosis, and autophagy formation in substance P-induced hyperactive bladder in rats.
abstract: Upregulation of substance P (SP) and neurokinin-1 receptor (NK1R) activation induces pro-inflammatory bladder hyperactivity through the PKC/ERK/NF-κB/ICAM-1/IL-33 signaling pathways to increase the leukocyte infiltration and adhesion leading to reactive oxygen species (ROS) production, autophagy, and apoptosis. l-Theanine is a unique non-protein-forming amino acid present in tea (Camellia sinensis [L.] O. Kuntze) with its antioxidant, anti-inflammatory, and relaxation effects to improve cognition, mood, gastric ulcer injury, and cerebral ischemia/reperfusion injury, and posttraumatic stress disorder. We explored the protective effect of l-theanine on SP-induced bladder hyperactivity.
  
  
  
  In urethane-anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, apoptosis-related Caspase 3/poly-(ADP-ribose)-polymerase (PARP), and autophagy-mediated LC3 II expression by Western blot, electrophoretic-mobility shift assay and immunohistochemistry, bladder ROS amount by a ultrasensitive chemiluminescence method, and possible ROS sources from the different leukocytes by specific stains in SP-evoked hyperactive bladder.
  
  
  
  l-Theanine dose-dependently depressed H2O2and HOCl activity in vitro. In urethane-anesthetized female Wistar rats, intra-arterial SP through NK1R activation increased voiding frequency (shortened intercontraction intervals) associated with the increase in bladder nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, Caspase 3/PARP-mediated apoptosis, LC3 II-mediated autophagy, ROS amount, neutrophils adhesion, CD68 (monocyte/macrophage) infiltration, and mast cells degranulation in the hyperactive bladder. Intragastrical l-theanine (15 mg/kg) twice daily for 2 weeks efficiently ameliorated all the enhanced parameters in the SP-treated hyperactive bladder.
  
  
  
  In conclusion, l-theanine through antioxidant and anti-inflammatory actions ameliorates SP-induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. Neurourol. Urodynam. 36:297-307, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.|Department of Traditional Chinese Medicine, Taipei City Hospital Linsen (Chinese Medicine) Branch, Taipei, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Tsai
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hong-Jeng
authors.initials: HJ
authors.lastname: Yu
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chien
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005971:Glutamates / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013373:Substance P; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D005971:Glutamates; C553108:Il33 protein, rat; D000067596:Interleukin-33; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; C026166:theanine; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: apoptosis; autophagy; inflammation; l-theanine; overactive bladder; reactive oxygen species