Molecular Mechanisms of Neuronal Death : Effects of Excitatory Amino Acids

考察了2-(羧基环丙基)甘氨酸(CCG)的药理性质。CCG的2S、3S、4S异构体(L-CCG-I)引起新生大鼠脊髓运动神经元去极化，对选择性N-甲基-D-天冬氨酸拮抗剂和环丙沙星不敏感，提示L-CCG-I可能是一种新型的谷氨酸激动剂。尽管已知的兴奋性氨基酸的去极化幅度增加或不变，但L-CCG-I引起的去极化幅度随浴液温度的降低而降低。L-CCG-I可增加大鼠海马神经元肌磷脂的水解率，并引起注射大鼠脑信使核糖核酸的非洲爪哇卵母细胞的氯离子振荡反应。因此，L-CCG-I是一种有效的代谢型谷氨酸激动剂。L-CCG-I组的去极化作用比反式-ACPD组更明显。代谢性谷氨酸受体的生理功能还没有很好的文献报道。L-CCG-I有望成为阐明这些受体的生理功能的有用工具。我们的初步研究表明，L-CCG-I更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。因此，与其他兴奋性氨基酸不同，L-CCG-I不会对哺乳动物中枢神经系统造成神经元损伤。MFPA对新生大鼠脊髓运动神经元的去极化作用强于油酸。全身给予MFPA可引起大鼠后肢伸展和边缘惊厥等特征性行为改变，对包括MFPA在内的海人酸衍生物的结合研究表明，存在两种海人藻酸受体。

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.