Inhibitory effect of the neuroprotective agent idebenone on arachidonic acid metabolism in astrocytes.
Idebenone, a compound with protective efficacy against neurotoxicity both in in vitro and in in vivo models, exists in two different oxidative states: the ubiquinol-derivative (reduced idebenone) and the ubiquinone-derivative (oxidised idebenone). In the present study, we have observed that both the redox forms of idebenone have a dose-dependent inhibitory effect on the enzymatic metabolism of arachidonic acid in astroglial homogenates (IC50 reduced idebenone: 1.76 +/- 0.86 microM; IC50 oxidised idebenone: 16.65 +/- 3.48 microM), while in platelets, they are apparently less effective (IC50 reduced idebenone: 18.28 +/- 4.70 microM; IC50 oxidised idebenone: > 1 mM). We have also observed that the oxidised form preferentially inhibited cyclooxygenase vs. lipoxygenase metabolism (IC50 ratio lipoxygenase/cyclooxygenase: 3.22), while the reduced form did not discriminate between the two pathways (IC50 ratio lipoxygenase/cyclooxygenase: 1.38). In this respect, the inhibitory action of reduced idebenone resembled that of the antioxidant nordihydroguaiaretic acid, while oxidised idebenone behaved similarly as indomethacin and piroxicam--two typical anti-inflammatory agents. Our results suggest the existence of two distinct mechanisms of action for the two redox forms of idebenone and a preferential action of the drug on arachidonic acid metabolism in the central nervous system.
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014451:Ubiquinone / Q000031:analogs & derivatives