Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice
Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice
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DOI：
10.1007/s10571-012-9900-9
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发表时间：
2013-04-01
影响因子：
4
通讯作者：
Petri, Susanne
中科院分区：
文献类型：
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作者：
Sun, Hui;Knippenberg, Sarah;Petri, Susanne
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(MN)死亡为特征的致死性神经退行性疾病。在本研究中，我们建立了一种纯化的胚胎MN的体外ALS模型，该模型来源于非转基因和突变的SOD1-G93A转基因小鼠，这是最常用的ALS动物模型。将MN与非转基因或突变型SOD1-G93A星形胶质细胞饲养层共同培养。用免疫细胞化学和钙显像法评估海人酸致兴奋毒性刺激后的细胞活性。然后，我们研究了N-乙酰-GLP-1(7-34)酰胺(N-Ac-GLP-1)的神经保护作用，N-Ac-GLP-1是一种长效的、N-末端乙酰化的、C-末端截短的类似物-胰高血糖素样肽-1(GLP-1)。GLP-1最初被研究为治疗II型糖尿病，基于其作为胰岛素促分泌剂的功能。我们在我们的体外系统中检测到N-Ac-GLP-1的神经保护作用，这可能归因于细胞内钙瞬变的减弱，不仅由于这些抗兴奋毒性能力，而且由于对ALS代谢缺陷的了解不断增加，N-Ac-GLP-1可能会对ALS产生积极的影响，该化合物代表了一种有趣的新候选化合物，可用于进一步的体内评估。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.