Morphology and ultrastructure of rat hippocampal formation after i.c.v. administration of N-acetyl-L-aspartyl-L-glutamate.
N-Acetyl-L-aspartyl-L-glutamate (NAAG) is one of the most abundant neuroactive compounds in the mammalian CNS. Our recent observations have suggested that NAAG administered into rat cerebral ventricles can cause neuronal death by apparently excitotoxic mechanisms that can be antagonized by the N-methyl-D-aspartate-receptor blockers and by ligands of metabotropic glutamate receptor of Group II. Therefore, the principal aim of the present study has been to use quantitative morphology, electron microscopy and terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling to study a dose- and time-dependence as well as regional distribution of neurodegeneration in hippocampi of rats after the intraventricular infusion of 0.25 micromol NAAG/ventricle and of equimolar doses of L-glutamate (L-GLU) and N-acetyl-L-aspartate (NAA), breakdown products of NAAG. The degenerative changes were observed after the infusion of 0.25 and 1.25 micromol of NAAG/ventricle, but not when a dose of 0.05 micromol of NAAG/ventricle was injected into each lateral cerebral ventricle. With a dose of 0.25 micromol of NAAG/ventricle the number of degenerated neurons reached a maximum on the fourth day after the infusion. The neuronal damage following bilateral administration of 0.25 micromol of NAAG/lateral cerebral ventricle exhibited features of a delayed neuronal degeneration, expressed mainly in the layer of dentate granule neurons. The degeneration was characterized on the basis of ultrastructural appearance and DNA-fragmentation. The morphological changes caused by L-glutamate and NAA were much smaller than those observed after the administration of NAAG and displayed a different pattern of regional distribution. The present findings suggest that NAAG can cause a loss of hippocampal neurons in vivo, apparently resulting from the neurotoxicity of NAAG itself.
Centre of Neuropsychiatric Studies and Prague Psychiatric Centre, Charles University, 3rd Medical Faculty, Ustavni 91, CZ-181 03 8 Prague, Czech Republic.
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L
Pliss
V J
VJ
Balcar
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Bubeníková
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J
Pokorný
T
T
Fitzgibbon
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F
St'astný
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D008297:Male; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D009479:Neuropeptides / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors
D004151:Dipeptides; D018690:Excitatory Amino Acid Agonists; D009479:Neuropeptides; D009498:Neurotoxins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C027172:isospaglumic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate