title: Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat.
abstract: Dementia and parkinsonism are late-onset symptoms associated with repetitive head injury, as documented in multiple contact-sport athletes. Clinical symptomatology is the likely phenotype of chronic degeneration and circuit disruption in the substantia nigra (SN). To investigate the initiating neuropathology, we hypothesize that a single diffuse brain injury is sufficient to initiate SN neuropathology including neuronal loss, vascular disruption and microglial activation, contributing to neurodegeneration and altered dopamine regulation. Adult, male Sprague-Dawley rats were subjected to sham or moderate midline fluid percussion brain injury. Stereological estimates indicated a significant 44% loss of the estimated total neuron number in the SN at 28-days post-injury, without atrophy of neuronal nuclear volumes, including 25% loss of tyrosine hydroxylase positive neurons by 28-days post-injury. Multi-focal vascular compromise occurred 1-2 days post-injury, with ensuing microglial activation (significant 40% increase at 4-days). Neurodegeneration (silver-stain technique) encompassed on average 21% of the SN by 7-days post-injury and increased to 29% by 28-days compared to sham (1%). Whole tissue SN, but not striatum, dopamine metabolism was altered at 28-days post-injury, without appreciable gene or protein changes in dopamine synthesis or regulation elements. Together, single moderate diffuse brain injury resulted in SN neurovascular pathology potentially associated with neuroinflammation or dopamine dysregulation. Compensatory mechanisms may preserve dopamine signaling acutely, but subsequent SN damage with aging or additional injury may expose clinical symptomatology of motor ataxias and dementia.
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: van Bregt
authors.forename: Theresa Currier
authors.initials: TC
authors.lastname: Thomas
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hinzman
authors.forename: Tuoxin
authors.initials: T
authors.lastname: Cao
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Guoying
authors.initials: G
authors.lastname: Bing
authors.forename: Greg A
authors.initials: GA
authors.lastname: Gerhardt
authors.forename: James R
authors.initials: JR
authors.lastname: Pauly
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lifshitz
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D055664:Electrochemical Techniques; D005786:Gene Expression Regulation / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D007546:Isoquinolines / Q000493:pharmacokinetics; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000175:diagnosis / Q000209:etiology; D009474:Neurons / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D007546:Isoquinolines; D008840:Microfilament Proteins; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D015102:3,4-Dihydroxyphenylacetic Acid; C069997:Tspo protein, rat; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine; D006719:Homovanillic Acid; C037850:PK 11195