Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity

Parkinson's disease (PD) is characterized mainly by a loss of nigrostriatal dopamine neurons. Thus far, the actual physiopathology of PD remains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respiratory chain, in various tissues of PD patients. Because most, if not all, of PD patients are treated chronically with levodopa, the precursor of dopamine, and because we have shown previously that catecholamines may alter mitochondrial respiration, we assessed the effects of chronic administration of levodopa on complex I activity in rat brain. We found that chronic administration of levodopa, at a dose used in PD patients, caused a significant reduction in complex I activity while it did not affect the activities of complex II, complex IV, and citrate synthase. Reduction in complex I activity correlated well with catecholamine innervation as the reduction was observed mainly in the striatum and substantia nigra and to a lesser extent in the frontal cortex but not in the cerebellum. Moreover, the levodopa-induced decrease of complex I activity was reversible since activities at 1, 3, and 7 days after the last injection showed a progressive return to control values. Incubation of whole brain mitochondria in vitro showed that both levodopa and dopamine inhibit complex I activity in a dose- and time-dependent manner. In contrast, other compounds such as homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effective. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various inhibitors of monoamine oxidase also prevented the effect of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)