ISHIDA Michiko The Tokyo Metropolitan Institute of Medical Acience, Pharmacology, Researcher, 薬理所究部門, 研究員 (90124437)
KWAK Shin Tokyo University, Neurology, Researcher, 医学部, 助手 (40160981)
|Budget Amount *help
¥5,900,000 (Direct Cost : ¥5,900,000)
Fiscal Year 1992 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1991 : ¥4,700,000 (Direct Cost : ¥4,700,000)
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.