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Animal models for amiotrophic lateral screrolis induced by an excitatory amino acid, acromelic acid.

由兴奋性氨基酸、丙烯酸诱导的肌萎缩侧索硬化动物模型。

基本信息

批准号：
03454244
负责人：
SHINOZAKI Haruhiko
金额：
$ 3.78万
依托单位：
The Tokyo Metropolitan Institute of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

It may be reasonable to assume that intrathecal administration of acromelic acid destroys selectively spinal motoneurons of the rat, because systemic administration of acromelic acid to the rat causes neuron damage of spinal inter-neurons confined to the lower spinal cord. At present, there is no experimental animal model of amiotrophic lateral screosis (ALS) in any species, therefore, acromelic acid would be expected to be a useful probe for elucidating this disease. Acromelic acid is a kainoid of natural origin, isolated from a Japanese poisonous mushroom, and now it is very difficult to synthesize and obtain a large amount of the sample. In addition, the sample of acromelic acid obtained was not pure, and its neurotoxicity was considerably weak, so it took a long time to refine it. So, for the time being, we electrophysiologically, neurologically and histologically studied the excitotoxicity induced by newly synthesized kainate derivatives which would be expected to cause selective neuron damage and as a result, we found a new potent excitatory amino acid of 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA) which was more potent in causing a depolarization than acromelic acid in the newborn rat spinal motoneurons. In addition to MFPA, a 4-(2-hydroxyphenly) derivative (HFPA) was also a potent kainate-like excitant. Thus, potent kainoids, such as acromelic acid, domoic acid, kainic acid, MFPA and HFPA, have lined up for the experiment of excitotoxicity. It was of great interest that these kainoids caused a significant depolarization of spinal motoneurons of the rat and induced characteristic neuron damage with regional difference. However, at present, there is no drug or method that induce selective neuron damage of motoneuron in the rat. We believe that long-term infusions of some kinds of kainoids at an extremely low concentration would cause selective neuron damage of motoneuron in the rat, although they are not yet found.

可以合理地假设，鞘内施用丙烯酸选择性地破坏大鼠的脊髓运动神经元，因为对大鼠全身施用丙烯酸导致局限于下脊髓的脊髓中间神经元的神经元损伤。目前，还没有任何一种动物的肌萎缩侧索硬化症（ALS）的实验动物模型，因此，丙烯酸有望成为阐明这种疾病的有用探针。丙烯醛酸是从日本毒蘑菇中分离出来的天然类红藻氨酸，目前很难合成和大量获得样品。另外，由于所得到的样品不纯，其神经毒性相当弱，因此需要较长的时间对其进行精制，因此，我们暂时从电生理学、神经学和组织学方面研究了新合成的红藻氨酸衍生物诱导的兴奋毒性，预期其会引起选择性神经元损伤，我们发现了一种新的强兴奋性氨基酸4-（2-甲氧基苯基）-2-羧基-3-吡咯烷乙酸（MFPA），它在引起新生大鼠脊髓运动神经元去极化方面比丙烯酸更强。除了MFPA之外，4-（2-羟基苯基）衍生物（HFPA）也是有效的红藻氨酸盐样兴奋剂。因此，有效的红藻氨酸，如丙烯酸，软骨藻酸，红藻氨酸，MFPA和HFPA，已排队用于兴奋毒性实验。这些海人素能引起大鼠脊髓运动神经元明显的去极化，并引起具有区域性差异的特征性神经元损伤。然而，目前还没有一种药物或方法能引起大鼠运动神经元的选择性损伤。我们认为，长期输注极低浓度的某些类海人藻酸盐会引起大鼠运动神经元的选择性神经元损伤，尽管尚未发现。