Characterization of chronic glutamate-mediated motor neuron toxicity in organotypic spinal cord culture prepared from ALS model mice
Characterization of chronic glutamate-mediated motor neuron toxicity in organotypic spinal cord culture prepared from ALS model mice
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DOI：
10.1016/j.neulet.2009.03.017
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发表时间：
2009-04-24
影响因子：
2.5
通讯作者：
Ito, Yoshihisa
中科院分区：
文献类型：
--
作者：
Kosuge, Yasuhiro;Sekikawa-Nishida, Kayo;Ito, Yoshihisa
肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，其特征是运动神经元的选择性丧失。尽管暴露于谷氨酸摄取抑制剂的器官型脊髓切片培养（OSCs）已被用作ALS的模型，用于筛选潜在的治疗药物。这类药物的开发很少。在本研究中，我们试图从G93A SOD1转基因小鼠（G93A）中建立osc，并利用胶质细胞系来源的神经营养因子（GDNF）在这些小鼠中表征运动神经元的特定细胞死亡途径。在GDNF存在的情况下，G93A小鼠和对照组小鼠osc中存活的神经元数量均显著增加。暴露于谷氨酸转运抑制剂三羟基天冬氨酸（THA） 14天后，G93A和对照小鼠的osc运动神经元丢失。在GDNF培养的osc中，tha诱导的运动神经元死亡在G93A小鼠中明显受到抑制，而在对照小鼠中则没有明显影响。此外，THA后G93A小鼠的OSCs中caspase-12的裂解形式增加，而对照组小鼠则没有，GDNF培养的OSCs中caspase-12的活化减弱。这些结果表明，THA诱导G93A小鼠OSCs运动神经元死亡的途径不仅涉及兴奋毒性，还涉及其他机制，caspase-12依赖性内质网应激途径在G93A小鼠脊髓神经元死亡中起作用。此外，由G93A小鼠ALS模型制备的osc可能为ALS提供一种合适的体外药物筛选模型。2009爱思唯尔爱尔兰有限公司版权所有。
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Although organotypic spinal slice cultures (OSCs) exposed to inhibitors of glutamate uptake have been used as a model of ALS for screening of potentially therapeutic drugs. little development of such drugs has been achieved. In the present study we attempted to establish OSCs from G93A SOD1 transgenic mice (G93A) and to characterize the specific cell death pathway in motoneurons using glial cell line-derived neurotrophic factor (GDNF) in these mice. In the presence of GDNF, the number of surviving neurons in the OSCs was dramatically increased in both G93A and control mice. Exposure to threo-hydroxyaspartate (THA), a glutamate transport inhibitor, for 14 days induced loss of motoneurons in OSCs in G93A and control mice. In OSCs cultured with GDNF, THA-induced motoneuronal death was significantly inhibited in G93A mice, whereas that in control mice was not significantly affected. Moreover, the cleaved form of caspase-12 was increased after THA in the OSCs in G93A but not in control mice, and the activation of caspase-12 was attenuated by OSCs cultured with GDNF These results suggest that the pathway responsible for motoneuronal death induced by THA in OSCs in G93A mice involves not only in excitotoxicity but also other mechanisms, and that the caspase-12-dependent ER stress pathway plays a role in spinal neuronal death in G93A mice. Moreover, OSCs prepared from the G93A mouse model of ALS may provide a suitable in vitro drug screening model for ALS. (C) 2009 Elsevier Ireland Ltd. All rights reserved.