Neuroprotective activity of glutamate receptor antagonists against soman-induced hippocampal damage: quantification with an omega 3 site ligand.
Previous investigations have indicated that the measurement of omega 3 (peripheral-type benzodiazepine) binding site densities could be of widespread applicability in the localization and quantification of neural tissue damage in the central nervous system. In the first step of the present study, the suitability of this approach for the assessment of soman-induced brain damage was validated. Autoradiographic study revealed marked increases of omega 3 site densities in several brain areas of convulsing rats 2 days after soman challenge. These increases were well-correlated with the pattern and the amplitude of neuropathological alterations due to soman and closely related to both glial reaction and macrophage invasion of the lesioned tissues. We then used this marker to assess, in mouse hippocampus, the neuroprotective activity against soman-induced brain damage of NBQX and TCP which are respective antagonists of non-NMDA and NMDA glutamatergic receptors. Injection of NBQX at 20 or 40 mg/kg 5 min prior to soman totally prevented the neuronal damage. Comparatively, TCP had neuroprotective efficacy when administered at 1 mg/kg 5 min prior to soman followed by a reinjection 1 h after. These results demonstrate that both NBQX and TCP afford a satisfactory neuroprotection against soman-induced brain damage. Since it is known that the neuropathology due to soman is closely seizure-related, the neuroprotective activities of NBQX and TCP are discussed in relation with the respective roles of non-NMDA and NMDA receptors in the onset and maintenance of soman-induced seizures.
Centre de Recherches, Service de Santé des Armées, La Tronche, France.
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Lallement
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Delamanche
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Pernot-Marino
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Baubichon
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Denoyer
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Carpentier
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Blanchet
D000818:Animals; D001345:Autoradiography; D048588:Benzoxazines; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists; D006624:Hippocampus / Q000473:pathology; D007546:Isoquinolines; D008024:Ligands; D008297:Male; D010078:Oxazines; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D012640:Seizures / Q000473:pathology; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity
D048588:Benzoxazines; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D008024:Ligands; D010078:Oxazines; D011810:Quinoxalines; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C028911:cresyl violet; C012058:tenocyclidine; D012999:Soman; D010622:Phencyclidine; C037850:PK 11195