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

可能有理由认为鞘内给药会选择性地破坏大鼠的脊髓运动神经元，因为全身给药会导致局限于下段脊髓的脊髓间神经元的神经元损伤。目前尚无实验动物模型存在于任何物种中，因此，丙烯酸可望成为阐明该疾病的有用的探针。丙烯酸是一种天然来源的海人藻类化合物，从日本有毒蘑菇中分离出来，现在很难合成和大量获得样品。此外，所获得的丙烯酸酯样品不纯，其神经毒性相当弱，因此需要很长时间才能提纯。因此，我们暂时从电生理学、神经学和组织学的角度研究了新合成的海人酸衍生物的兴奋性毒性，发现了一种新的强效的兴奋性氨基酸4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic酸(MFPA)，它比顶体酸更能引起新生大鼠脊髓运动神经元的去极化。除MFPA外，4-(2-羟基苯基)衍生物(HFPA)也是一种有效的海人酸样兴奋剂。因此，强效的海藻酸，如海藻酸、软骨藻酸、海人藻酸、MFPA和HFPA，已排队进行兴奋性毒性实验。值得注意的是，这些红藻氨酸引起了大鼠脊髓运动神经元的显着去极化，并引起了具有区域性差异的特征性神经元损伤。但目前尚无药物或方法诱导大鼠运动神经元选择性损伤。我们认为，长期输注极低浓度的某些类型的红藻氨酸会导致大鼠运动神经元的选择性损伤，尽管目前还没有发现这种损伤。

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.