CHRONIC LEVODOPA ADMINISTRATION ALTERS CEREBRAL MITOCHONDRIAL RESPIRATORY-CHAIN ACTIVITY

Parkinson's disease (PD) is characterized mainly by a loss of nigrostr iatal dopamine neurons. Thus far, the actual physiopathology of PD rem ains uncertain, although recent studies have found decreased activity of complex I, one of the enzymatic units of the mitochondrial respirat ory 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 chroni c administration of levodopa on complex I activity in rat brain. We fo und that chronic administration of levodopa, at a dose used in PD pati ents, caused a significant reduction in complex I activity while it di d not affect the activities of complex II, complex IV, and citrate syn thase. Reduction in complex I activity correlated well with catecholam ine innervation as the reduction was observed mainly in the striatum a nd substantia nigra and to a lesser extent in the frontal cortex but n ot in the cerebellum. Moreover, the levodopa-induced decrease of compl ex I activity was reversible since activities at 1, 3, and 7 days afte r the last injection showed a progressive return to control values. In cubation of whole brain mitochondria in vitro showed that both levodop a and dopamine inhibit complex I activity in a dose- and time-dependen t manner. in contrast, other compounds such as homovanillic acid, 3,4- dihydroxyphenylacetic acid, and 3-O-methyl-dopa were minimally effecti ve. Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex I. Various i nhibitors of monoamine oxidase also prevented the effect of dopamine. In agreement with a critical role of monoamine oxidase in this effect in vitro, we observed that noncatecholamine substrates of this enzyme such as serotonin and beta-phenylethylamine were potent inhibitors of complex I. However, autoxidation may also be involved in this process because the effect of levodopa, 6-hydroxydopa, and 6-hydroxydopamine o n complex I activity was only partially suppressed by monoamine oxidas e inhibitors. These observations demonstrate that the chronic administ ration of levodopa can cause alterations in mitochondrial respiratory chain activity in rats that are most likely related to an oxidative st ress provoked by the increase in dopamine turnover. We suggest that th is mechanism may exaggerate a mitochondrial defect already present in the brains of PD patients and thus may play a role in the progression of PD.