{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:14:33Z","timestamp":1790471673183,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2004,10,8]],"date-time":"2004-10-08T00:00:00Z","timestamp":1097193600000},"content-version":"vor","delay-in-days":3994,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[1993,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010induced 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\u2010 and time\u2010 dependent manner. In contrast, other compounds such as homovanillic acid, 3,4\u2010dihydroxyphenylacetic acid, and 3\u2010<jats:italic>O<\/jats:italic>\u2010methyl\u2010dopa 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. 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 \u03b2\u2010phenylethylamine were potent inhibitors of complex I. However, autoxidation may also be involved in this process because the effect of levodopa, 6\u2010hydroxydopa, and 6\u2010hydroxydopamine on complex I activity was only partially suppressed by monoamine oxidase inhibitors. These observations demonstrate that the chronic administration of levodopa can cause alterations in mitochondrial respiratory chain activity in rats that are most likely related to an oxidative stress provoked by the increase in dopamine turnover. We suggest that this 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.<\/jats:p>","DOI":"10.1002\/ana.410340515","type":"journal-article","created":{"date-parts":[[2005,1,1]],"date-time":"2005-01-01T00:27:57Z","timestamp":1104539277000},"page":"715-723","source":"Crossref","is-referenced-by-count":116,"title":["Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity"],"prefix":"10.1002","volume":"34","author":[{"given":"Serge","family":"Przedborski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vernice","family":"Jackson\u2010Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uday","family":"Muthane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali B.","family":"Naini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Fahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,10,8]]},"reference":[{"key":"e_1_2_1_2_2","first-page":"2143","volume-title":"Cecil's textbook of medicine","author":"Fahn S","year":"1988"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320616"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1990.tb02325.x"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1990.tb05809.x"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410260606"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320612"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(91)90311-T"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(85)90146-8"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-198612000-00001"},{"key":"e_1_2_1_11_2","first-page":"1276","article-title":"Catecholamines inhibit mitochondrial complex I activity in rat brain","volume":"17","author":"Jackson\u2010Lewis V","year":"1991","journal-title":"Soc Neurosci Abstr"},{"key":"e_1_2_1_12_2","first-page":"18","article-title":"Regulation of energy functions of mitochondria with biogenic amines","volume":"36","author":"Medvedev A","year":"1990","journal-title":"Vopr Med Khim"},{"key":"e_1_2_1_13_2","volume-title":"Statistical power analysis for the behavioral sciences","author":"Cohen J","year":"1987"},{"key":"e_1_2_1_14_2","volume-title":"Statistical methods","author":"Snedecor GW","year":"1980"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-198403000-00005"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(89)90790-5"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)62854-6"},{"key":"e_1_2_1_18_2","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1523\/JNEUROSCI.12-05-01658.1992","article-title":"Transgenic mice with increased Cu\/Zn\u2010superoxide dismutase activity are resistant to N\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine\u2010induced neurotoxicity","volume":"12","author":"Przedborski S","year":"1992","journal-title":"J Neurosci"},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(69)13005-0"},{"key":"e_1_2_1_21_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-198905000-00025"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(67)10048-7"},{"key":"e_1_2_1_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb09789.x"},{"key":"e_1_2_1_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb09431.x"},{"key":"e_1_2_1_25_2","first-page":"12","article-title":"The cerebral metabolism of L\u2010dihydroxyphenylalanine. 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