Wang Xin, Min Su, Xie Fei, Yang Jun, Li Liang, Chen Jingyuan
Department of Anesthesiology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Anesthesiology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Biochem Biophys Res Commun. 2018 Feb 5;496(2):260-266. doi: 10.1016/j.bbrc.2018.01.020. Epub 2018 Jan 5.
Sepsis-induced neuromuscular dysfunction results from up-regulation of the expression of γ- and α7-nicotinic acetylcholine receptors (nAChR). Although glial cell derived neurotrophic factor (GDNF) has been implicated in repairing and supporting neurons, little is known about the effects of GDNF on demyelination of nerves in sepsis. In this study, we tested the hypothesis that GDNF could alleviate sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nAChR in an experimental rat model of neuromyopathy. Rats were randomly divided into a sham group and a sepsis group. Levels of inflammatory factors, muscle function, and nicotinic acetylcholine receptors were tested in rats after cecal ligation and puncture (CLP). At 24 h after CLP, GDNF was injected around the sciatic nerve of sepsis rats, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining was used to detect the expression of nAChRs. GDNF and its downstream effector (Erk1/2 and GFR-α), neuregulin-1 (NRG-1) and γ- and α7-nAChR were measured using Western blot analysis. The expression of GDNF reached a minimum at 24 h after CLP. Compared with the sham group, the release of cytokines and the expression of γ- and α7-nAChR were significantly increased in the sepsis group. The administration of GDNF significantly alleviated sepsis-induced neuromuscular dysfunction, as well as reducing the expression of γ- and α7-nAChR. In addition, the expression of Erk1/2, GFR-α, NRG-1 were significantly increased after GDNF treatment. GDNF administration may improve patient outcomes by reducing the demyelination of nerves and the expression of γ- and α7-nAChR.
脓毒症诱导的神经肌肉功能障碍是由γ-和α7-烟碱型乙酰胆碱受体（nAChR）表达上调所致。尽管胶质细胞源性神经营养因子（GDNF）与神经元的修复和支持有关，但关于GDNF对脓毒症中神经脱髓鞘的影响知之甚少。在本研究中，我们在实验性大鼠神经肌肉病模型中检验了GDNF可通过降低γ-和α7-nAChR的表达来减轻脓毒症诱导的神经肌肉功能障碍这一假说。将大鼠随机分为假手术组和脓毒症组。在盲肠结扎和穿刺（CLP）后检测大鼠的炎症因子水平、肌肉功能和烟碱型乙酰胆碱受体。CLP后24小时，在脓毒症大鼠的坐骨神经周围注射GDNF，通过酶联免疫吸附测定（ELISA）检测细胞因子，并使用免疫荧光染色检测nAChRs的表达。使用蛋白质免疫印迹分析测量GDNF及其下游效应物（Erk1/2和GFR-α）、神经调节蛋白-1（NRG-1）以及γ-和α7-nAChR。CLP后24小时GDNF的表达降至最低。与假手术组相比，脓毒症组细胞因子的释放以及γ-和α7-nAChR的表达显著增加。给予GDNF可显著减轻脓毒症诱导的神经肌肉功能障碍，并降低γ-和α7-nAChR的表达。此外，GDNF治疗后Erk1/2、GFR-α、NRG-1的表达显著增加。给予GDNF可能通过减少神经脱髓鞘以及γ-和α7-nAChR的表达来改善患者预后。
