Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-D-aspartate induce permanent neural damage.
Despite extensive evidence for the neurotoxic effects of excitatory amino acids (EAA) in the brain little is known about their neurotoxic action in the spinal cord. In this study we attempted to produce differential lesions of spinal neurons by pretreating mice, intrathecally, with high concentrations of the EAA: N-methyl-D-aspartate (NMDA), quisqualate and kainate. Pharmacological, behavioral and histological consequences were examined 1, 3, 7 and, in some cases, 30 days after pretreatment. A single, intrathecal, injection of high concentrations of quisqualate and kainate but not NMDA, resulted in damage to spinal cord neurons. The highest concentrations of these agonists produced, in some animals, a massive, non-selective destruction of neurons within the lumbar spinal cord, accompanied by complete paralysis of the hindlimbs. Pretreatment with lower concentrations of intrathecal kainate or quisqualate produced damage to spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal cord to EAA, as seen from the decrease in biting behavior elicited by intrathecal EAA. The neurotoxic effects of quisqualate were completely blocked by the quisqualate/kainate receptor antagonist glutamylaminomethylsulphonate (GAMS), but not the NMDA antagonist 2-amino-5-phosphovalerate. GAMS attenuated the effects of kainate only partially.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000374:Aggression / Q000187:drug effects*; D000818:Animals; D005973:Glutamine / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009498:Neurotoxins; D010146:Pain / Q000503:physiopathology; D010243:Paralysis / Q000139:chemically induced; D016318:Quisqualic Acid / Q000633:toxicity*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology
D009498:Neurotoxins; D005973:Glutamine; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D016318:Quisqualic Acid; C042626:gamma-glutamylaminomethylsulfonic acid; D007608:Kainic Acid