title: Involvement of lipid peroxidation and inhibitory mechanisms on ischemic neuronal damage in gerbil hippocampus: quantitative autoradiographic studies on second messenger and neurotransmitter systems.
abstract: We investigated, to examine the involvement of lipid peroxidation and inhibitory mechanisms, a novel lipid peroxidation inhibitor (KB-5666) and a GABAA receptor-effector (pentobarbital) on ischemic neuronal damage and the alterations in the second messenger and neurotransmitter systems in Mongolian gerbils by means of morphology and in vitro receptor autoradiography. Quantitative receptor autoradiography visualized binding sites for [3H]inositol 1,4,5-trisphosphate, [3H]forskolin, [3H]phorbol 12,13-dibutyrate, [3H]isradipine (PN200-110), [3H]N6-cyclohexyl-adenosine, and [3H]quinuclidinyl benzilate indicating binding sites for inositol 1,4,5-trisphosphate, forskolin, protein kinase C, L-type calcium channels (or dihydropyridine binding sites), adenosine A1, and muscarinic cholinergic receptors, respectively. In the morphological study, KB-5666, 10 and 50 mg/kg, i.v., 5 min before ischemia, protected against ischemic neuronal damage to the hippocampal CA1 subfield following 5 min of bilateral carotid artery occlusion in a dose-dependent manner. Pentobarbital, 30 mg/kg, i.v., 5 min before ischemia, also had a protective effect. In receptor autoradiographic studies, all receptor bindings decreased significantly in the CA1 subfield seven days after ischemia. In particular, [3H]inositol 1,4,5-trisphosphate binding in the CA1 subfield was completely lost after ischemia. [3H]Inositol 1,4,5-trisphosphate and [3H]forskolin binding decreased as early as 6 h after ischemia. In the CA3 subfield, [3H]inositol 1,4,5-trisphosphate, [3H]PN200-110, and [3H]N6-cyclohexyladenosine bindings decreased seven days after ischemia. In the dentate gyrus, [3H]inositol 1,4,5-trisphosphate binding decreased seven days after ischemia. KB-5666 and pentobarbital prevented reductions in these receptor bindings in the CA1 subfield at 6 h and seven days after ischemia. These results indicate that KB-5666 and pentobarbital protect the brain from both structural and functional damage after ischemia, and that lipid peroxidation and inhibitory mechanisms may play a pivotal role in the neuronal damage of the hippocampal CA1 subfield after ischemia.
authors.affiliation: Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Araki
authors.forename: H
authors.initials: H
authors.lastname: Onodera
authors.forename: K
authors.initials: K
authors.lastname: Kogure
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000503:physiopathology*; D015220:Calcium Channels / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000378:metabolism; D005849:Gerbillinae; D006624:Hippocampus / Q000503:physiopathology*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D010424:Pentobarbital / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate; D011799:Quinazolines / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D002712:Chlorides; D007473:Ion Channels; D018377:Neurotransmitter Agents; D011799:Quinazolines; D011963:Receptors, GABA-A; C066472:KB 5666; D005576:Colforsin; C027513:N(6)-cyclohexyladenosine; D015240:Phorbol 12,13-Dibutyrate; D011813:Quinuclidinyl Benzilate; D015544:Inositol 1,4,5-Trisphosphate; D010424:Pentobarbital; D000241:Adenosine