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.