Prevention of hippocampus neuronal damage in ischemic gerbils by a novel lipid peroxidation inhibitor (quinazoline derivative).
We investigated the effect of a novel quinazoline derivative (KB-5666), a lipid peroxidation inhibitor, on ischemic neuronal damage using Mongolian gerbils. The animals were sacrificed 7 or 30 days after 5 min of forebrain ischemia induced by bilateral common carotid artery occlusion. Morphologic changes, a microtubule-associated protein 2 (MAP2) immunohistochemical study and quantitative autoradiographic study using [3H]phorbol 12, 13-dibutyrate ([3H]PDBu) were evaluated in the hippocampus after ischemia. KB-5666 (3-50 mg/kg, i.v.) showed protective effects against neuronal death of the CA1 subfield 5 min before ischemia, immediately or 1 hr after ischemia, but not 4 hr after ischemia. KB-5666 (i.p.) also showed protective effects in a dose-dependent manner immediately after ischemia. Furthermore, KB-5666 dose-dependently prevented a marked decrease in microtubule-associated protein 2 immunoreactivity in the dendritic fields of the CA1 pyramidal cells after ischemia. The [3H]PDBu binding activity in the stratum oriens and the stratum lacunosum-moleculare of the CA1 subfield was reduced by 19 and 30%, respectively, 7 days after ischemia. [3H]PDBu binding sites were unchanged in the stratum oriens in the CA3 subfield. By contrast, in the molecular layer of the dentate gyrus, the [3H]PDBu binding activity increased by 15%. KB-5666 (i.v.) prevented a decrease in the [3H]PDBu binding activity in the stratum oriens and stratum lacunosum-moleculare of the CA1 subfield and an increase in the molecular layer of the dentate gyrus. These histologic, immunohistochemical and receptor-autoradiographic data indicate that KB-5666 protects the brain from both cellular and functional consequences of ischemia.
Hara
H
H
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Kogure
K
K
D000818:Animals; D001345:Autoradiography; D002545:Brain Ischemia / Q000473:pathology*; D005609:Free Radicals; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010424:Pentobarbital / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*
D005609:Free Radicals; D008869:Microtubule-Associated Proteins; D011799:Quinazolines; C066472:KB 5666; D015240:Phorbol 12,13-Dibutyrate; D010424:Pentobarbital