权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Mechanisms of Neuronal Death : Effects of Excitatory Amino Acids

神经元死亡的分子机制：兴奋性氨基酸的作用

基本信息

批准号：
01571261
负责人：
SHINOZAKI Haruhiko
金额：
$ 1.34万
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 (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

Pharmacological properties of 2-(carboxycyclopropyl) glycine (CCG) were examined. The 2S, 3S, 4S isomer of CCG (L-CCG-I) caused a depolarization of newborn rat spinal motoneurons which was insensitive to selective NMDA antagonists and CNQX, suggesting that L-CCG-I may be a novel-type glutamate agonist. The amplitude of the depolarization induced by L-CCG-I decreased when the temperature of bathing fluid was reduced, in spite of the fact that that of known excitatory amino acids was increased or unchanged. L-CCG-I increased the inositophosphtide hydrolysis in the rat hippocampal neuron, and caused oscillatory chloride responses in Xenopus oocytes injected with rat brain mRNA. Therefore, it is concluded that L-CCG-I is a potent metabotropic glutamate agonist. The depolarization induced by L-CCG-I was more marked than that by trans-ACPD. The physiological function of metabotropic glutamate receptors have not yet well documented. L-CCG-I would be expected to be a useful tool for elucidation of the physiological function of these receptors. Our preliminary examination demonstrated that L-CCG-I preferred to reduce the monosynaptic reflex in the newborn rat spinal cord, probably because of presynaptic inhibition. Therefore, it is reasonable to presume that L-CCG-I does not cause neuron damage in the mammalian central nervous system, unlike other excitatory amino acids.A kainate derivative, 4-methoxyphenyl-2-carboxy-3-pyrroridineacetic acid (MFPA), was synthesized and its pharmacological properties were examined. MFPA was more potent than acromelic acid in causing a depolarization of newborn rat spinal motoneurons. Systemic administration of MFPA to the rat induced characteristic behavioral change which composed of the extension of the hindlimbs and limbic seizures, and binding studies of kainate derivatives including MFPA suggested that there are two kinds of kainate receptors.

研究了2-羧基环丙基甘氨酸（CCG）的药理学性质。CCG的2S，3S，4S异构体（L-CCG-I）引起对选择性NMDA拮抗剂和CNQX不敏感的新生大鼠脊髓运动神经元去极化，提示L-CCG-I可能是一种新型的谷氨酸激动剂。L-CCG-I引起的去极化幅度随浴液温度的降低而降低，而已知的兴奋性氨基酸的去极化幅度则增加或不变。L-CCG-I增加大鼠海马神经元肌醇磷脂的水解，并引起注射大鼠脑mRNA的爪蟾卵母细胞的振荡氯反应。因此，可以得出结论，L-CCG-I是一种有效的代谢型谷氨酸激动剂。L-CCG-I引起的去极化作用比trans-ACPD更明显。代谢型谷氨酸受体的生理功能还没有很好的记录。L-CCG-I有望成为阐明这些受体生理功能的有用工具。我们的初步研究表明，L-CCG-I倾向于减少新生大鼠脊髓的单突触反射，可能是由于突触前抑制。合成了一种红藻氨酸衍生物4-甲氧基苯基-2-羧基-3-吡咯烷乙酸（4-methoxyphenyl-2-carboxy-3-pyrroidineacetate，MFPA），并对其药理学性质进行了研究。MFPA对新生大鼠脊髓运动神经元的去极化作用强于丙烯酸。MFPA全身给药可引起大鼠后肢伸展和边缘系统癫痫发作等特征性行为改变，包括MFPA在内的红藻氨酸衍生物的结合研究表明，红藻氨酸受体存在两种类型。