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Exploiting the advantage of cell culture systems, we demonstrated that microglia, but not astroglia, significantly enhanced the progression of MPTP\u2010induced dopaminergic neurodegeneration. Characterization of the temporal relationship between neurodegeneration and microglial activation demonstrates that reactive microgliosis resulting from MPTP\u2010initiated neuronal injury, but not direct activation, underlies the microglia\u2010enhanced MPTP neurotoxicity. Mechanistically, through the release of NADPH oxidase\u2010derived reactive oxygen species, microglia contribute to the progressive neuronal damage. Among the factors measured, the production of extracellular superoxide was the most prominent. NADPH oxidase inhibitor, apocynin, attenuated MPTP\u2010induced dopaminergic neurodegeneration only in the presence of glia. More importantly, dopaminergic neurons from mice lacking NADPH oxidase, a key enzyme for superoxide production in immune cells, are significantly more resistant to MPTP neurotoxicity than those from wild\u2010type controls, and microglia dictate the resistance. This study demonstrates that reactive microgliosis triggered by MPTP\u2010induced neuronal injury and NADPH oxidase\u2010mediated superoxide production in microglia constitute an integral component of MPTP neurotoxicity. This study also suggests that NADPH oxidase may be a promising target for therapeutic interventions in Parkinson's disease.<\/jats:p>","DOI":"10.1096\/fj.03-0109fje","type":"journal-article","created":{"date-parts":[[2003,8,4]],"date-time":"2003-08-04T20:40:05Z","timestamp":1060029605000},"page":"1-22","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":219,"title":["Critical role of microglial NADPH oxidase\u2010derived free radicals in the in vitro MPTP model of Parkinson's disease"],"prefix":"10.1096","volume":"17","author":[{"given":"Hui-Ming","family":"Gao","sequence":"first","affiliation":[{"name":"Neuropharmacology Section Laboratory of Pharmacology and Chemistry National Institute of Environmental Health Sciences National Institutes of Health  Research Triangle Park North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Neuropharmacology Section Laboratory of Pharmacology and Chemistry National Institute of Environmental Health Sciences National Institutes of Health  Research Triangle Park North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neuropharmacology Section Laboratory of Pharmacology and Chemistry National Institute of Environmental Health Sciences National Institutes of Health  Research Triangle Park North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jau-Shyong","family":"Hong","sequence":"additional","affiliation":[{"name":"Neuropharmacology Section Laboratory of Pharmacology and Chemistry National Institute of Environmental Health Sciences National Institutes of Health  Research Triangle Park North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2003,8]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.41.2_Part_1.202"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.51.2_Suppl_2.S25"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1993.tb13610.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1991.tb02134.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.22.1.219"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-200108000-00009"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.035048"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00928.x"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(08)61770-7"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/70978"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0742213.x"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)00704-8"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00021-0"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251341998"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-05-01763.2002"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(95)00578-1"},{"key":"e_1_2_6_18_1","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1523\/JNEUROSCI.19-09-03440.1999","article-title":"FcepsilonRII\/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells","volume":"19","author":"Hunot S.","year":"1999","journal-title":"J. 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