L-Theanine Inhibits Proinflammatory PKC/ERK/ICAM-1/IL-33 Signaling, Apoptosis, and Autophagy Formation in Substance P-Induced Hyperactive Bladder in Rats
L-Theanine Inhibits Proinflammatory PKC/ERK/ICAM-1/IL-33 Signaling, Apoptosis, and Autophagy Formation in Substance P-Induced Hyperactive Bladder in Rats
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DOI：
10.1002/nau.22965
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发表时间：
2017-02-01
影响因子：
2
通讯作者：
Chien, Chiang-Ting
中科院分区：
文献类型：
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作者：
Tsai, Wen-Hsin;Wu, Chung-Hsin;Chien, Chiang-Ting
目的：P物质（SP）和神经激肽-1受体（NK 1 R）激活的上调通过PKC/ERK/NF-κ B/ICAM-1/IL-33信号通路诱导促炎性膀胱过度活动，以增加白细胞浸润和粘附，从而导致活性氧（ROS）产生、自噬和凋亡。L-茶氨酸是茶叶中特有的非蛋白质氨基酸。O. Kuntze）具有抗氧化、镇静和放松作用，可改善认知、情绪、胃溃疡损伤、脑缺血/再灌注损伤和创伤后应激障碍。探讨L-茶氨酸对SP诱导的膀胱过度活动的保护作用。研究方法：在麻醉的雌性Wistar大鼠中，我们探讨了收缩描记图，盆神经活动，促炎性PKC/ERK/NF-κ B/ICAM-1/IL-33信号，凋亡相关的Caspase 3/poly-1，（ADPribose）-聚合酶（PARP）和自噬介导的LC 3 II表达，通过Western印迹、免疫印迹-迁移率变动分析和免疫组织化学，通过超灵敏的化学发光方法测定膀胱ROS量，并通过特异性染色探讨SP诱发的膀胱过度活动症中不同白细胞的ROS来源。结果：L-茶氨酸在体外呈剂量依赖性地抑制H2 O2和HOCl活性。在麻醉的雌性Wistar大鼠中，动脉内SP通过NK 1 R激活增加排尿频率与膀胱神经活性增加、促炎性PKC/ERK/NF-kB/ICAM-1/IL-33信号传导、Caspase 3/PARP介导的凋亡、LC 3 II介导的自噬、ROS量、中性粒细胞粘附、CD 68（单核细胞/巨噬细胞）浸润和肥大细胞脱粒。灌胃L-茶氨酸（15 mg/kg），每天两次，持续2周，有效地改善了SP治疗的膀胱过度活动症的所有增强参数。结论：总之，L-茶氨酸通过抗氧化和抗炎作用，通过抑制促炎性PKC/ERK/NF-kB/ICAM-1/IL-33信号传导、氧化应激、膀胱神经过度活动、细胞凋亡和自噬来改善SP诱导的膀胱过度活动。(C)2016 Wiley Periodicals，Inc.
Aims: Upregulation of substance P (SP) and neurokinin-1 receptor (NK1R) activation induces pro-inflammatory bladder hyperactivity through the PKC/ERK/NF-kappa B/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, antiinflammatory, 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. Methods: In urethane-anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF-kB/ICAM-1/IL-33 signaling, apoptosis-related Caspase 3/poly-(ADPribose)- 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. Results: L-Theanine dose-dependently depressed H2O2 and 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-kB/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. Conclusions: In conclusion, L-theanine through antioxidant and anti-inflammatory actions ameliorates SP-induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF-kB/ICAM-1/IL-33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. (C) 2016 Wiley Periodicals, Inc.