Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injuryReportar como inadecuado




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Journal of Translational Medicine

, 12:130

First Online: 15 May 2014Received: 16 December 2013Accepted: 14 March 2014DOI: 10.1186-1479-5876-12-130

Cite this article as: Zhang, H., Wu, F., Kong, X. et al. J Transl Med 2014 12: 130. doi:10.1186-1479-5876-12-130

Abstract

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 both in vivo and in vitro. The level of cell apoptosis was determined by TUNEL in vivo and Flow cytometry in vitro. Relative downstream signals Akt-GSK-3β and ERK1-2were also analyzed with or without inhibitors in 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 model in 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.

KeywordsNerve growth factor Endoplasmic reticulum stress Spinal cord injury Apoptosis Akt-GSK-3β ERK1-2 Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-12-130 contains supplementary material, which is available to authorized users.

Hongyu Zhang, Fenzan Wu contributed equally to this work.

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Autor: Hongyu Zhang - Fenzan Wu - Xiaoxia Kong - Jie Yang - Huijun Chen - Liancheng Deng - Yi Cheng - Libing Ye - Sipin Zhu - Xi

Fuente: https://link.springer.com/







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