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山东大学学报(医学版) ›› 2017, Vol. 55 ›› Issue (7): 17-22.doi: 10.6040/j.issn.1671-7554.0.2016.1674

• 基础医学 • 上一篇    下一篇

NR2B通过mBDNF参与肠易激综合征内脏高敏感的发生

张文雪,徐丽东,张明明,郭传国,左秀丽   

  1. 山东大学齐鲁医院消化内科, 山东 济南 250012
  • 收稿日期:2016-12-19 出版日期:2017-07-10 发布日期:2017-07-10
  • 通讯作者: 左秀丽. E-mail:zuoxiuli@sina.com E-mail:zuoxiuli@sina.com
  • 基金资助:
    国家自然科学基金(81370495)

NR2B contributes to visceral hypersensitivity in irritable bowel syndrome via mBDNF

ZHANG Wenxue, XU Lidong, ZHANG Mingming, GUO Chuanguo, ZUO Xiuli   

  1. Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Received:2016-12-19 Online:2017-07-10 Published:2017-07-10

摘要: 目的 在神经系统,NMDA受体(NMDARs)NR2B亚基参与内脏高敏感的发生,本研究探讨在肠黏膜,该NR2亚型是否通过mBDNF(mBDNF)参与肠易激综合征内脏高敏感的发生。 方法 共纳入32例参与者,检测肠黏膜NR2B及mBDNF的表达水平。用Pearson线性相关分析NR2B与mBDNF表达水平的关系;用Spearman秩相关分析mBDNF表达水平与腹部疼痛评分的关系;以NMDA受体激动剂、NMDA受体阻滞剂、NR2B特异性阻滞剂干预细胞,ELISA法检测培养基中mBDNF蛋白表达水平的变化。 结果 腹泻型肠易激综合征( IBS-D)组肠黏膜组织NR2B及mBDNF蛋白表达水平均明显高于对照组(NR2B: 90.22±30.79 vs 63.47±28.19, P=0.016; mBDNF:89.91±20.95 vs 56.53±22.25, P<0.001),且两者表达水平呈正相关。mBDNF表达水平与腹部疼痛评分呈正相关。NMDA受体活化后可诱导mBDNF表达增加,该作用可完全被NMDA受体阻滞剂、NR2B特异性阻滞剂抑制。 结论 NR2B亚基通过诱导mBDNF的表达参与IBS-D患者内脏高敏感的发生。

关键词: NR2B, 内脏高敏感, 肠易激综合征, 成熟脑源性神经营养因子

Abstract: Objective In the nervous system, N-methyl-D-aspartate receptors(NMDARs)subunit NMDA receptor 2B(NR2B)is involved in visceral hypersensitivity. This study aims to investigate if colonic mucosal NR2B contributes to visceral hypersensitivity in irritable bowel syndrome via mature brain-derived neurotrophic factor(mBDNF). Methods A total of 32 participants were included. Colonic mucosal NR2B subunits and mBDNF expressions were detected. The relationship between the NR2B and mBDNF expressions was analyzed with Pearson correlation analysis. The relationship between mBDNF expression and abdominal pain scores was analyzed with Spearman correlation analysis. After administration of NMDARs agonist, NMDARs antagonist and NR2B subunit antagonist, the expression of mBDNF in cell culture supernatant was assessed with ELISA. Results NR2B and mBDNF expressions were significantly increased in colonic mucosa of IBS-D patients(NR2B: 90.22±30.79 vs 63.47±28.19, P=0.016; mBDNF: 89.91±20.95 vs 56.53±22.25, P<0.001). NR2B expression was positively correlated with mBDNF expression. Furthermore, mBDNF expression was positively correlated with abdominal pain scores. The activation of NMDAR induced mBDNF expression, which could be completely inhibited by NMDARs antagonist and NR2B subunit antagonist. Conclusion NR2B contributes to visceral hypersensitivity in IBS-D via mBDNF.

Key words: Irritable bowel syndrome, NR2B, Mature brain-derived neurotrophic factor, Visceral hypersensitivity

中图分类号: 

  • R574
[1] Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function[J]. Pharmacol Rev, 2010, 62(3): 405-496.
[2] Seo JH, Fox JG, Peek RM, et al. N-methyl D-aspartate channels link ammonia and epithelial cell death mechanisms in Helicobacter pylori Infection[J]. Gastroenterology, 2011, 141(6): 2064-2075.
[3] Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease[J]. Nat Rev Neurosci, 2013, 14(6): 383-400.
[4] Ferguson HJ, Wragg JW, Ward S, et al. Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer[J]. Oncotarget, 2016, 7(15): 20440-20454.
[5] Fukuchi M, Tabuchi A, Kuwana Y, et al. Neuromodulatory effect of Galphas-or Galphaq-coupled G-protein-coupled receptor on NMDA receptor selectively activates the NMDA receptor/Ca2+/calcineurin/cAMP response element-binding protein-regulated transcriptional coactivator 1 pathway to effectively induce brain-derived neurotrophic factor expression in neurons[J]. J Neurosci, 2015, 35(14): 5606-5624.
[6] Park H, Popescu A, Poo MM. Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP[J]. Neuron, 2014, 84(5): 1009-1022.
[7] Qi Q, Chen F, Zhang W, et al. Colonic N-methyl-D-aspartate receptor contributes to visceral hypersensitivity in irritable bowel syndrome[J]. J Gastroenterol Hepatol, 2017, 32(4): 828-836.
[8] Yu YB, Zuo X, Zhao QJ, et al. Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome[J]. Gut, 2012, 61(5): 685-694.
[9] Fan J, Wu X, Cao Z, et al. Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats[J]. Gastroenterology, 2009, 136(5): 1732-1740 e3.
[10] Willert RP, Woolf CJ, Hobson AR, et al. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate receptor[J]. Gastroenterology, 2004, 126(3): 683-692.
[11] Wu X, Gao J, Yan J, et al. Role for NMDA receptors in visceral nociceptive transmission in the anterior cingulate cortex of viscerally hypersensitive rats[J]. Am J Physiol Gastrointest Liver Physiol, 2008, 294(4): G918-927.
[12] Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders[J]. Gastroenterology, 2006, 130(5): 1480-1491.
[13] Talley NJ,Phillips SF, Melton J 3rd, et al. A patient questionnaire to identify bowel disease[J]. Ann Intern Med, 1989, 111(8): 671-674.
[14] Wang P, Du C, Chen FX, et al. BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit[J]. Sci Rep, 2016, 6: 20320. doi: 10.1038/srep20320.
[15] Li CY, Li SC. Treatment of irritable bowel syndrome in China: a review[J]. World J Gastroenterol, 2015, 21(8): 2315-2322.
[16] Barbara G, Cremon C, Annese V, et al. Randomised controlled trial of mesalazine in IBS[J]. Gut, 2016, 65(1): 82-90.
[17] Corsetti M, Van Oudenhove L, Tack J. The quest for biomarkers in IBS-where should it lead us?[J]. Neurogastroenterol Motil, 2014, 26(12): 1669-1676.
[18] Paoletti P. Molecular basis of NMDA receptor functional diversity[J]. Eur J Neurosci, 2011, 33(8): 1351-1365.
[19] Reijerkerk A, Kooij G, van der Pol SM, et al. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier[J]. J Neurochem, 2010, 113(2): 447-453.
[20] Wang P, Chen FX, Du C, et al. Increased production of BDNF in colonic epithelial cells induced by fecal supernatants from diarrheic IBS patients[J]. Sci Rep, 2015, 5: 10121. doi: 10.1038/srep10121.
[21] Maqsood R, Stone TW. The gut-brain axis, BDNF, NMDA and CNS disorders[J]. Neurochem Res, 2016, 41(11): 2819-2835.
[22] Marosi K, Kim SW, Moehl K, et al. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons[J]. J Neurochem, 2016, 139(5): 769-781.
[23] 陈飞雪, 于岩波, 王鹏, 等. 脑源性神经营养因子对小鼠回肠及结肠平滑肌收缩活动的影响及其机制[J]. 山东大学学报(医学版), 2012, 50(4): 42-46. CHEN Feixue, YU Yanbo, WANG Peng, et al. Brain derived neurotrophic factor influences contractile activity in the isolated ileum and colon of mice[J]. Journal of Shandong University(Health Sciences), 2012, 50(4): 42-46.
[24] 赵栋燕, 于岩波, 左秀丽. 脑源性神经营养因子在小鼠肠黏膜屏障中的作用[J]. 山东大学学报(医学版), 2016, 54(7): 1-5. ZHAO Dongyan, YU Yanbo, ZUO Xiuli. Brain derived neurotrophic factor modulates intestinal barrier integrity in mice[J]. Journal of Shandong University(Health Sciences), 2016, 54(7): 1-5.
[25] Yu YB, Zhao DY, Qi QQ, et al. BDNF modulates intestinal barrier integrity through regulating the expression of tight junction proteins[J]. Neurogastroenterol Motil, 2017, 29(3). doi: 10.1111/nmo.12967. Epub 2016 Oct 17.
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