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Parkinson's disease (PD) is a neurodegenerative disorder pathogenically related to oxidative stress and shows GSH depletion in the substantia nigra (SN). Herein, we report that 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (MPTP)\u2010treated mice, an experimental model of PD, showed reduced motor activity, reduced GSH contents, EAAC1 translocation to the membrane and increased levels of nitrated EAAC1. These changes were reversed by pre\u2010administration of n\u2010acetylcysteine (NAC), a membrane\u2010permeable cysteine precursor. Pretreatment with 7\u2010nitroindazole, a specific neuronal nitric oxide synthase inhibitor, also prevented both GSH depletion and nitrotyrosine formation induced by MPTP. Pretreatment with hydrogen peroxide, <jats:sc>l<\/jats:sc>\u2010aspartic acid \u03b2\u2010hydroxamate or 1\u2010methyl\u20104\u2010phenylpyridinium reduced the subsequent cysteine increase in midbrain slice cultures. Studies with chloromethylfluorescein diacetate, a GSH marker, demonstrated dopaminergic neurons in the SN to have increased GSH levels after NAC treatment. These findings suggest that oxidative stress induced by MPTP may reduce neuronal cysteine uptake, via EAAC1 dysfunction, leading to impaired GSH synthesis, and that NAC would exert a protective effect against MPTP neurotoxicity by maintaining GSH levels in dopaminergic neurons.<\/jats:p>","DOI":"10.1111\/j.1460-9568.2007.05979.x","type":"journal-article","created":{"date-parts":[[2010,7,19]],"date-time":"2010-07-19T15:36:26Z","timestamp":1279553786000},"page":"20-30","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Oxidative stress on EAAC1 is involved in MPTP\u2010induced glutathione depletion and motor dysfunction"],"prefix":"10.1111","volume":"27","author":[{"given":"Koji","family":"Aoyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuko","family":"Matsumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Watabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Nakaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,12,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69031196.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(98)00064-X"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1609"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-09-05559.1994"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/S0021-9258(19)85901-X","article-title":"Transport interaction of 1\u2010cystine and 1\u2010glutamate in human diploid fibroblasts in culture","volume":"255","author":"Bannai S.","year":"1980","journal-title":"J. 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