Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury.
Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury.
复制标题
神经生长因子通过抑制内质网应激诱导的脊髓损伤大鼠神经元凋亡促进功能恢复
DOI：
10.1186/1479-5876-12-130
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发表时间：
2014-05-15
影响因子：
7.4
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Zhang H;Wu F;Kong X;Yang J;Chen H;Deng L;Cheng Y;Ye L;Zhu S;Zhang X;Wang Z;Shi H;Fu X;Li X;Xu H;Lin L;Xiao J
应激诱导的髓质网（ER）凋亡在包括脊髓损伤（SCI）在内的多种疾病中起重要作用。神经生长因子（NGF）具有神经保护作用，可促进脊髓损伤的恢复，但内质网应激诱导的细胞凋亡与NGF在脊髓损伤中的治疗作用的关系尚不清楚。方法成年雌性Sprague-Dawley大鼠暴露脊柱，在T9椎体处行椎板切除术，并用血管夹进行中度挫伤。脊髓损伤后，用0.9% NaCl稀释NGF原液，以20 μg/kg/d静脉滴注，此后每天1次，直至处死。分别于1d、3d、7d、14d处死大鼠。采用21点BBB （Basso-Beattie-Bresnahan）运动量表、斜面测验和足迹分析对脊髓损伤模型大鼠进行运动活动测试。Western blot分析内质网应激相关蛋白CHOP、GRP78、caspase-12在体内和体外的表达情况。采用TUNELin和体外流式细胞术检测细胞凋亡水平。在体外分析Akt/GSK-3β和erk1 /2的相对下游信号。结果内质网应激诱导的细胞凋亡参与了脊髓损伤模型大鼠的损伤过程。神经生长因子可促进模型大鼠脊髓损伤区运动功能恢复，增加神经元存活。通过TUNEL检测，NGF可减少神经元凋亡，抑制caspase-3级联的激活。内质网应激诱导的凋亡应答蛋白CHOP、GRP78和caspase-12被NGF抑制。同时，NGF也增加了生长相关蛋白43 （GAP43）的表达。在体外内质网应激细胞模型中，NGF可激活下游信号Akt/GSK-3β和ERK1/2。结论NGF在脊髓损伤恢复中的神经保护作用可能与其通过激活下游信号抑制内质网应激诱导的细胞死亡有关，这也提示了NGF翻译药物在参与调节慢性内质网应激的中枢神经系统损伤中的新发展趋势。
BackgroundEndoplasmic reticulum (ER) stress-induced apoptosis plays a major role in various diseases, including spinal cord injury (SCI). Nerve growth factor (NGF) show neuroprotective effect and improve the recovery of SCI, but the relations of ER stress-induced apoptosis and the NGF therapeutic effect in SCI still unclear.MethodsYoung adult female Sprague-Dawley rats’s vertebral column was exposed and a laminectomy was done at T9 vertebrae and moderate contusion injuries were performed using a vascular clip. NGF stock solution was diluted with 0.9% NaCl and administered intravenously at a dose of 20 μg/kg/day after SCI and then once per day until they were executed. Subsequently, the rats were executed at 1d, 3 d, 7d and 14d. The locomotor activities of SCI model rats were tested by the 21-point Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test and footprint analysis. In addition, Western blot analysis was performed to identify the expression of ER-stress related proteins including CHOP, GRP78 and caspase-12 bothin vivoandin vitro.The level of cell apoptosis was determined by TUNELin vivoand Flow cytometryin vitro. Relative downstream signals Akt/GSK-3β and ERK1/2were also analyzed with or without inhibitorsin vitro.ResultsOur results demonstrated that ER stress-induced apoptosis was involved in the injury of SCI model rats. NGF administration improved the motor function recovery and increased the neurons survival in the spinal cord lesions of the model rats. NGF decreases neuron apoptosis which measured by TUNEL and inhibits the activation of caspase-3 cascade. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 are inhibited by NGF treatment. Meanwhile, NGF administration also increased expression of growth-associated protein 43 (GAP43). The administration of NGF activated downstream signals Akt/GSK-3β and ERK1/2 in ER stress cell modelin vitro.ConclusionThe neuroprotective role of NGF in the recovery of SCI is related to the inhibition of ER stress-induced cell death via the activation of downstream signals, also suggested a new trend of NGF translational drug development in the central neural system injuries which involved in the regulation of chronic ER stress.
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影响因子：
5.3
作者：
Hu, Xinhua;Cai, Jie;Yang, Jun;Smith, George M.
通讯作者：
Smith, George M.
影响因子：
6.2
作者：
Ohri, Sujata Saraswat;Maddie, Melissa A.;Whittemore, Scott R.
通讯作者：
Whittemore, Scott R.
影响因子：
4.4
作者：
de Oliveira, Marcos Roberto;da Rocha, Ricardo Fagundes;Fonseca Moreira, Jose Claudio
通讯作者：
Fonseca Moreira, Jose Claudio
影响因子：
3.7
作者：
Lan A;Liao X;Mo L;Yang C;Yang Z;Wang X;Hu F;Chen P;Feng J;Zheng D;Xiao L
通讯作者：
Xiao L
影响因子：
1.8
作者：
Manni, Luigi;Rocco, Maria Luisa;Aloe, Luigi
通讯作者：
Aloe, Luigi