The effect of l-deprenyl, d-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism leading to an adaptive increase in superoxide dismutase activity

Abstract

l-Deprenyl is an irreversible monoamine oxidase-B inhibitor with a complex pharmacological profile. For instance, l-deprenyl administration to rat and mice increases cytosolic CuZn- and mitochondrial Mn-superoxide dismutase activities in the striatum. CuZn- and Mn-superoxide dismutase are enzymes involved in defense against superoxide (O 2 ⋅) radicals. Hence, an increase in CuZn- and Mn-superoxide dismutase activities is suggestive of oxidative stress. The major intracellular site of O 2 ⋅ radicals formation is the mitochondrial respiratory chain. Several reports indicated that alterations in mitochondrial respiratory functions enhances O 2 ⋅ production. We observed that l-deprenyl induced a dose-dependent inhibition of oxygen (O 2) consumption (state 3) during ATP synthesis in presence of complex I (pyruvate and malate) and complex II (succinate) substrates in fresh mitochondrial preparations. d-Deprenyl produced a similar inhibitory profile whereas MDL72974, a selective monoamine oxidase-B inhibitor, was less effective. Administration of d-deprenyl or MDL72974 to mice resulted in an increase in both striatal CuZn- and -Mn-superoxide dismutase activities. Accordingly, we propose that the impairment of mitochondrial respiratory functions which stimulates O 2 ⋅ formation could modulate CuZn- and Mn-superoxide dismutase activities, through a mechanism that appears to be independent of monoamine oxidase-B inhibition.