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Recently, the peroxisome proliferation-activated receptor gamma (PPAR\u03b3) agonist pioglitazone has been demonstrated to be neuroprotective in animal models of neurodegeneration. The present study investigates the vulnerability of the nigrostriatal system after TBI, and intervention with pioglitazone treatment. Adult male Sprague-Dawley rats were subjected to sham or moderate midline fluid percussion brain injury (mFPI), followed by an intraperitoneal injection of 10\u2009mg\/kg pioglitazone or vehicle beginning 30\u2009min after the injury and subsequently every 24\u2009h for 5 days. Following injury, pro-inflammatory cytokines and chemokine were acutely increased in the striatum and substantia nigra within 6\u2009h. Dopaminergic axonal damage and microglial activation were revealed using immunohistochemistry in the medial forebrain bundle at 1 day post-injury. Microglial activation identified by Iba1 and OX-6 immunostaining was persistently increased in the substantia nigra pars compacta 7 to 28 days post-injury. Further, brain injury induced significant dopaminergic neuronal loss, which was quantified by tyrosine hydroxylase immunostaining and retrograde fluorescent tracer fluorogold labeling in the nigra at 28 days. Loss of neurons was accompanied by increased extracellular dopamine (DA) turnover in the striatum, indicating enhanced dopaminergic activity in functional compensation after nigrostriatal damage. Strikingly, pioglitazone treatment greatly attenuated microglial activation and improved dopaminergic neuronal survival in the nigrostriatal system, which may promote locomotor recovery. These results suggest that interventions that attenuate secondary inflammation could be a feasible therapeutic treatment to improve outcome after TBI.<\/jats:p>","DOI":"10.1089\/neu.2015.4361","type":"journal-article","created":{"date-parts":[[2016,5,3]],"date-time":"2016-05-03T22:49:44Z","timestamp":1462315784000},"page":"414-422","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":57,"title":["Pioglitazone Attenuates Neuroinflammation and Promotes Dopaminergic Neuronal Survival in the Nigrostriatal System of Rats after Diffuse Brain Injury"],"prefix":"10.1177","volume":"34","author":[{"given":"Mei","family":"Liu","sequence":"first","affiliation":[{"name":"University of Kentucky College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D.","family":"Bachstetter","sequence":"additional","affiliation":[{"name":"University of Kentucky College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne A.","family":"Cass","sequence":"additional","affiliation":[{"name":"University of Kentucky College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lifshitz","sequence":"additional","affiliation":[{"name":"Arizona State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoying","family":"Bing","sequence":"additional","affiliation":[{"name":"University of Kentucky College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2017,1,15]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.282.10.989"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25945"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.870060306"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.870060202"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws307"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.003"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2010.1723"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1179\/1743132813Y.0000000289"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24830"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.11.087"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/34178"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2000.00110.x"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1690453"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.07.046"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2012.03.010"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.58.9.778"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.71.3.388"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(20010201)49:2<276::AID-ANA53>3.0.CO;2-5"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00990.x"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2038-05.2005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2010.10.003"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2015.01.003"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0b013e31819fcd1b"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04327.x"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcts.2003.12.017"},{"key":"e_1_3_3_27_2","volume-title":"The Rat Brain in Stereotaxic Coordinates","author":"Paxinos G.","year":"1998","unstructured":"Paxinos G., , and Watson C. 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