Sedative-hypnotic properties and mitochondrial effects of coenzyme Q2 in mice.

BACKGROUND

Anesthetics are fascinating drugs capable of inducing reversible unconsciousness. Functional targets of these agents exist within mitochondria and disruption of bioenergetic capacity plays a role in mediating the anesthetic response. Recently, ubiquinone-5 (coenzyme Q1)(Ub5 or CoQ1), a short-chain coenzyme Q (CoQ) analog with a single isoprene unit, was identified as a novel anesthetic with a mitochondrial mechanism. Benzoquinones share an identical head group yet differ in the length of their isoprenoid tail. It is unknown if other CoQ analogs exhibit anesthetic properties or how side-chain length affects their activity. Here, we hypothesized that CoQ2, an analog with two isoprene tail units, would act as a sedative-hypnotic and that its mitochondrial biological activity would differ from Ub5 (CoQ1).

METHODS

Behavioral phenotype was assessed in mice using behavioral and neurophysiological approaches. We measured activity within isolated mitochondria using polarography and spectrophotometry and attempted to identify source of proton leak using pharmacological inhibitors.

RESULTS

CoQ2 induced brief and reversible brain quiescence shortly after injection and caused a precipitous decline in the mitochondrial membrane potential due to excessive mitochondrial proton leak combined with electron transport chain inhibition. Unlike Ub5 (CoQ1), however, there was a latency to onset of CoQ2-induced hypnosis, effective CoQ2 doses were relatively higher, and duration of CoQ2-mediated unconsciousness was relatively longer than that previously reported for Ub5 (CoQ1). Furthermore, the source of proton leak differed between analogs.

CONCLUSIONS

The comparable anesthetic effects likely relate to the benzoquinone head group shared between molecules while the disparities are likely due to the length of the isoprenoid tail.