Neuron damage induced by some potent kainoids and neuroprotective action of new agonists for metabotropic glutamate receptors.
Selective and characteristic neuron damage induced by acromelic acid, a potent kainate analogue, was investigated in comparison to a kainate-induced one. A single systemic injection of acromelic acid A caused behavioral and pathological effects distinct from those seen after systemic kainate. There was an initial marked tonic extension of the rat hindlimb, often followed by convulsions and, in surviving rats, by a transient flaccid paralysis and ultimately, a persistent spastic paraplegia. Pathological examination suggested specific lesions of interneurons in the lower spinal cord with little or no damage to the hippocampal neurons preferentially affected by systemic kainate. Another agonist for kainate-type receptors, which is not a kainoid, demonstrated neurological symptoms and neuron damage quite similar to those of kainate. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were described with special reference to kainate excitotoxicity. Intraventricular DCG-IV, a new agonist, caused selective neuron damage in the cingulate cortex and the hippocampal subiculum at relatively high doses, but other agonists did not cause neuron damage in the rat. DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by kainate-type agonists.
Shinozaki
H
H
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Japan.
D000600:Amino Acids, Dicarboxylic / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D046508:Culture Techniques; D003521:Cyclopropanes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000187:drug effects* / Q000502:physiology; D009468:Neuromuscular Diseases / Q000139:chemically induced* / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000600:Amino Acids, Dicarboxylic; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; C082313:2-(2,3-dicarboxycyclopropyl)glycine; C035261:(alpha-carboxycyclopropyl)glycine; C051743:acromelic acid A; D007608:Kainic Acid; D005998:Glycine