The effect of L-deprenyl, D-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism leading to an adaptive increase in superoxide dismutase activity.
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 (O2.) radicals. Hence, an increase in CuZn- and Mn-superoxide dismutase activities is suggestive of oxidative stress. The major intracellular site of O2. radicals formation is the mitochondrial respiratory chain. Several reports indicated that alterations in mitochondrial respiratory functions enhances O2. production. We observed that L-deprenyl induced a dose-dependent inhibition of oxygen (O2) 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 O2. formation could modulate CuZn- and Mn-superoxide dismutase activities, through a mechanism that appears to be independent of monoamine oxidase-B inhibition.
Thiffault
C
C
Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada.
Quirion
R
R
Poirier
J
J
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002082:Butylamines / Q000494:pharmacology*; D002417:Cattle; D002531:Cerebellum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004912:Erythrocytes / Q000201:enzymology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D012642:Selegiline / Q000494:pharmacology*; D013237:Stereoisomerism; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism*
D000498:Allyl Compounds; D000978:Antiparkinson Agents; D002082:Butylamines; D008996:Monoamine Oxidase Inhibitors; C058000:mofegiline; D012642:Selegiline; D013482:Superoxide Dismutase; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine