Inhibitory effect of the neuroprotective agent idebenone on arachidonic acid metabolism in astrocytes

Idebenone, a compound with protective efficacy against neurotoxicity both i n 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 en zymatic metabolism of arachidonic acid in astroglial homogenates (IC50 redu ced idebenone: 1.76 +/- 0.86 mu M; IC50 oxidised idebenone: 16.65 +/- 3.48 mu M), while in platelets, they are apparently less effective (IC50 reduced idebenone: 18.28 +/- 4.70 mu M; IC50 oxidised idebenone: > 1 mM). We have also observed that the oxidised form preferentially inhibited cyclooxygenas e vs. lipoxygenase metabolism (IC50 ratio lipoxygenase/cyclooxygenase: 3.22 ), while the reduced form did not discriminate between the two pathways (IC 50 ratio lipoxygenase/cyclooxygenase: 1.38). In this respect, the inhibitor y action of reduced idebenone resembled that of the antioxidant nordihydrog uaiaretic 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 metabol ism in the central nervous system. (C) 1999 Elsevier Science B.V. All right s reserved.