Molecular Mechanisms of Neuronal Death : Effects of Excitatory Amino Acids

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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.