GUANABENZ DELAYS THE ONSET OF DISEASE SYMPTOMS, EXTENDS LIFESPAN, IMPROVES MOTOR PERFORMANCE AND ATTENUATES MOTOR NEURON LOSS IN THE SOD1 G93A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS
GUANABENZ DELAYS THE ONSET OF DISEASE SYMPTOMS, EXTENDS LIFESPAN, IMPROVES MOTOR PERFORMANCE AND ATTENUATES MOTOR NEURON LOSS IN THE SOD1 G93A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS
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GUANABENZ 在肌萎缩侧索硬化症 SOD1 G93A 小鼠模型中延迟疾病症状的发生、延长寿命、改善运动性能并减轻运动神经元损失
DOI：
10.1016/j.neuroscience.2014.03.047
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发表时间：
2014-09-26
期刊：
影响因子：
3.3
通讯作者：
Feng, H. -L.
中科院分区：
文献类型：
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作者：
Jiang, H. -Q.;Ren, M.;Feng, H. -L.
肌萎缩侧索硬化症(ALS)是一种以运动皮质、脑干和脊髓运动神经元丢失为特征的持续进行性神经退行性疾病。目前，这种致命的疾病还没有治愈的方法。尽管ALS神经细胞死亡的机制仍不清楚，但越来越多的证据支持内质网(ER)应激在ALS发病机制中的关键作用。最近的报道显示，一种新型的真核细胞起始因子2α(eIF2α)去磷酸化抑制剂，具有抗病毒特性，可以减轻内质网应激，减少瘫痪和神经退行性变。然而，在肌萎缩侧索硬化症的小鼠模型中，尚未评估愈创木酚治疗肌萎缩侧索硬化症的治疗潜力。在本研究中，对一种广泛使用的ALS小鼠模型进行了治疗，该模型表达铜锌超氧化物歧化酶-1(SOD1)，并在93位(G93A)发生甘氨酸到丙氨酸突变。结果表明，给药后能显著延长SOD1G93A雌性小鼠的寿命，延缓疾病症状的出现，改善运动能力，减轻运动神经元的丢失。此外，免疫印迹结果显示，愈创木酚显著增加磷酸化eIF2α(P-eIF2α)蛋白水平，而不影响总的eIF2α蛋白水平。结果还显示，内质网伴侣葡萄糖调节蛋白78(Bip/GRP78)和另外两个内质网应激途径的标志物-激活转录因子6α(ATF6α)和肌醇要求酶1(IRE1)的水平显著下降。此外，Ganabenz还能提高SOD1G93A小鼠抗凋亡B细胞淋巴瘤/LEWKMIA-2(Bcl2)的蛋白水平，下调促凋亡蛋白C/EBP同源蛋白(CHOP)、Bcl2相关X蛋白(Bax)和细胞色素C的水平。我们的研究结果表明，Ganabenz可能是治疗ALS的一种新的候选药物，ALS是一种致命的人类疾病，其潜在机制涉及通过延长eIF2α的磷酸化来减轻内质网应激和线粒体应激。(C)2014年，爱思唯尔有限公司代表IBRO出版。
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease characterized by the loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently, there is no cure for this lethal disease. Although the mechanism underlying neuronal cell death in ALS remains elusive, growing evidence supports a crucial role of endoplasmic reticulum (ER) stress in the pathogenesis of ALS. Recent reports show that guanabenz, a novel inhibitor of eukaryotic initiation factor 2 alpha (eIF2 alpha) dephosphorylation, possesses anti-prion properties, attenuates ER stress and reduces paralysis and neurodegeneration in mTDP-43 Caenorhabditis elegans and Danio rerio models of ALS. However, the therapeutic potential of guanabenz for the treatment of ALS has not yet been assessed in a mouse model of ALS. In the present study, guanabenz was administered to a widely used mouse model of ALS expressing copper zinc superoxide dismutase-1 (SOD1) with a glycine to alanine mutation at position 93 (G93A). The results showed that the administration of guanabenz significantly extended the lifespan, delayed the onset of disease symptoms, improved motor performance and attenuated motor neuron loss in female SOD1 G93A mice. Moreover, western blotting results revealed that guanabenz dramatically increased the levels of phosphorylated-eIF2 alpha (P-eIF2 alpha) protein, without affecting total eIF2 alpha protein levels. The results also revealed a significant decrease in the levels of the ER chaperone glucose-regulated protein 78 (BiP/Grp78) and markers of another two ER stress pathways, activating transcription factor 6 alpha (ATF6 alpha) and inositol-requiring enzyme 1 (IRE1). In addition, guanabenz increased the protein levels of anti-apoptotic B cell lymphoma/lewkmia-2 (Bcl-2), and down-regulated the pro-apoptotic protein levels of C/EBP homologous protein (CHOP), Bcl-2-associated X protein (BAX) and cytochrome C in SOD1 G93A mice. Our findings indicate that guanabenz may represent a novel therapeutic candidate for the treatment of ALS, a lethal human disease with an underlying mechanism involving the attenuation of ER stress and mitochondrial stress via prolonging eIF2 alpha phosphorylation. (C) 2014 Published by Elsevier Ltd. on behalf of IBRO.