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Previously, we have shown that deficiency of TNF receptors protects against MPTP\u2010induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF\u2010\u03b1 in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP\u2010induced expression of microglia\u2010derived factors, TNF\u2010\u03b1, MCP\u20101, and IL\u20101\u03b1, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF\u2010\u03b1 in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor\u2010deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade\u2010B staining (to identify degenerating neurons) and decreased microtubule\u2010associated protein\u20102 (MAP\u20102) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF\u2010\u03b1 exerts a neurotrophic\/neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and\/or activity of microglia and microglia\u2010derived factors may influence the region\u2010specific role for this cell type. Taken together, our results are indicative of a region\u2010specific and dual role for TNF\u2010\u03b1 in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus.\u2010Sriram, K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster, M. I., O'Callaghan, J. P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP\u2010induced neurotoxicity: role of TNF\u2010\u03b1.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    20, 670\u2013682 (2006)\n                  <\/jats:p>","DOI":"10.1096\/fj.05-5106com","type":"journal-article","created":{"date-parts":[[2006,3,31]],"date-time":"2006-03-31T13:37:51Z","timestamp":1143812271000},"page":"670-682","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":201,"title":["Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP\u2010induced neurotoxicity: role of TNF\u2010\u03b1\n                    <sup>1<\/sup>"],"prefix":"10.1096","volume":"20","author":[{"given":"Krishnan","family":"Sriram","sequence":"first","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna M.","family":"Matheson","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley A.","family":"Benkovic","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane B.","family":"Miller","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Luster","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"O'Callaghan","sequence":"additional","affiliation":[{"name":"Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,4]]},"reference":[{"key":"e_1_2_3_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)80737-N"},{"key":"e_1_2_3_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(91)90490-K"},{"key":"e_1_2_3_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-199210000-00004"},{"key":"e_1_2_3_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(94)90684-X"},{"key":"e_1_2_3_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(94)90746-3"},{"key":"e_1_2_3_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(96)12706-3"},{"key":"e_1_2_3_8_1","doi-asserted-by":"publisher","DOI":"10.2302\/kjm.45.239"},{"key":"e_1_2_3_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/1359-6101(96)00003-2"},{"key":"e_1_2_3_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(98)00083-5"},{"key":"e_1_2_3_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.440070113"},{"key":"e_1_2_3_12_1","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1097\/00002093-199803001-00001","article-title":"Glial cell reactions in neurodegenerative diseases: pathophysiology and therapeutic interventions","volume":"12","author":"McGeer P. 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