title: Pioglitazone Attenuates Neuroinflammation and Promotes Dopaminergic Neuronal Survival in the Nigrostriatal System of Rats after Diffuse Brain Injury.
abstract: Increasing evidence suggests that traumatic brain injury (TBI) may raise the risk of developing late-onset Parkinson's disease (PD). Recently, the peroxisome proliferation-activated receptor gamma (PPARγ) 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 mg/kg pioglitazone or vehicle beginning 30 min after the injury and subsequently every 24 h for 5 days. Following injury, pro-inflammatory cytokines and chemokine were acutely increased in the striatum and substantia nigra within 6 h. 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.
authors.affiliation: 1 Department of Anatomy and Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: 2 Sanders-Brown Center on Aging, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.affiliation: 1 Department of Anatomy and Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cass
authors.affiliation: 3 BARROW Neurological Institute at Phoenix Children's Hospital; Department of Child Health, University of Arizona College of Medicine, Phoenix, Arizona; Phoenix Veteran Affairs Healthcare System, Phoenix, Arizona; Interdisciplinary Graduate Program in Neuroscience, Arizona State University , Tempe, Arizona.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
authors.affiliation: 1 Department of Anatomy and Neurobiology, University of Kentucky College of Medicine , Lexington, Kentucky.
authors.forename: Guoying
authors.initials: G
authors.lastname: Bing
mesh_terms: D000818:Animals; D000070625:Brain Injuries, Diffuse / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018836:Inflammation Mediators; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Parkinson's disease; brain injury; pioglitazone; substantia nigra