Effects of idebenone on metabolism of monoamines and cyclic AMP formation in rats.
Idebenone, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, at a dose of 100 mg/kg (i.p.) markedly increased the level of 5-hydroxyindole-3-acetic acid (5-HIAA) in several brain regions without affecting monoamine contents in normal rats. In rats with cerebral ischemia, idebenone (10 mg/kg, i.p.) normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-hydroxytryptamine (serotonin, 5-HT) biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) decreased the levels of 5-HT to one-third of the control level 24 h after administration. Idebenone (10, 30, or 100 mg/kg, i.p.), administered 24 h after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreased in the hippocampus, diencephalon and brain stem in a dose-dependent manner. Idebenone (100 mg/kg, i.p.) stimulated the release of 5-HT in the dorsal hippocampus as determined by in vivo differential pulse voltammetry. Idebenone, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of hippocampus and diencephalon, and the formation of cyclic AMP in a concentration-dependent manner in rat diencephalon slice. This stimulation was almost completely blocked by methysergide, a 5-HT receptor blocker. Idebenone slightly and PCA markedly inhibited 5-HT uptake into hippocampus slices. The mechanism of the 5-HT releasing actions of idebenone in the hippocampal slices may be mediated through endogenous calcium. These results suggest that idebenone has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon, and brain stem of rats.
Nagai
Y
Y
Central Research Division, Takeda Chemical Industries, Ltd. Osaka, Japan.
Narumi
S
S
Kakihana
M
M
Yamazaki
N
N
Nagaoka
A
A
Nagawa
Y
Y
D000818:Animals; D016227:Benzoquinones; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D010134:Fenclonine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D008297:Male; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives
D016227:Benzoquinones; D015306:Biogenic Monoamines; D007211:Indoles; D011809:Quinones; D014451:Ubiquinone; C026785:5-hydroxyindole; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000242:Cyclic AMP; C036619:idebenone; D010134:Fenclonine