Effects of idebenone (CV-2619) on metabolism of monoamines, especially serotonin, in the brain of normal rats and rats with cerebral ischemia

Abstract

The effects of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone, CV-2619) on the contents, turnover, release and uptake of monoamines, especially serotonin (5-HT), in various brain regions of Wistar rats were studied in vivo and in vitro. In normal rats, an intraperitoneal (i.p.) dose of 100 mg/kg of CV-2619 had no significant effect on the levels of norepinephrine (NE), dopamine (DA) and their metabolites, and 5-HT in the brain regions examined, but it increased the levels of 5-hydroxyindole-3-acetic acid (5-HIAA), the main metabolite of 5-HT, in many brain regions. In rats with cerebral ischemia, a low dose (10 mg/kg, i.p.) of CV-2619 normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-HT biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.), decreased the levels of 5-HT in all brain regions to one-third of the control levels 24 hr after administration in normal rats. CV-2619 (10, 30 or 100 mg/kg, i.p.), administered 24 hr after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreases in the hippocampus, diencephalon and brain stem in a dose-dependent manner. In vitro CV-2619, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of the hippocampus and diencephalon. CV-2619 slightly inhibited and PCA markedly inhibited 5-HT uptake into hippocampal slices. The mechanism of the 5-HT releasing action of CV-2619 in hippocampal slices seems to be mediated through endogenous calcium. These results suggest that CV-2619 has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon and brain stem of rats.