title: Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat.
abstract: Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury.
authors.affiliation: From the Program in Neuroscience, Drexel University College of Medicine, Philadelphia, Pennsylvania (LAH, RR); Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia Pennsylvania (JWH); and Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania (RR).
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Hanlon
authors.affiliation: From the Program in Neuroscience, Drexel University College of Medicine, Philadelphia, Pennsylvania (LAH, RR); Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia Pennsylvania (JWH); and Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania (RR).
authors.forename: Jimmy W
authors.initials: JW
authors.lastname: Huh
authors.affiliation: From the Program in Neuroscience, Drexel University College of Medicine, Philadelphia, Pennsylvania (LAH, RR); Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia Pennsylvania (JWH); and Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania (RR). Ramesh.raghupathi@drexelmed.edu.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D000097382:CD68 Molecule
chemical_list: D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D005452:Fluoresceins; D008840:Microfilament Proteins; D008911:Minocycline; C100745:Aif1 protein, rat; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C435731:fluoro jade
keywords: Abusive head trauma; Cognition; Inflammation; Microglia; Neurodegeneration; Pediatric.
references.citation: J Neurotrauma. 2013 Mar 1;30(5):324-38
references.pmid: 23078348
references.citation: Stroke. 2002 Mar;33(3):795-801
references.pmid: 11872906
references.citation: J Neuropathol Exp Neurol. 2007 Nov;66(11):989-1001
references.pmid: 17984681
references.citation: Nature. 2002 May 2;417(6884):74-8
references.pmid: 11986668
references.citation: J Neurotrauma. 1998 Sep;15(9):693-705
references.pmid: 9753217
references.citation: Brain Res. 1992 Jul 10;585(1-2):335-9
references.pmid: 1511317
references.citation: J Neurotrauma. 2010 May;27(5):911-21
references.pmid: 20166806
references.citation: J Neurosurg. 2006 Oct;105(4 Suppl):287-96
references.pmid: 17328279
references.citation: J Neurosci Methods. 2009 Jun 30;181(1):36-44
references.pmid: 19393692
references.citation: J Neurotrauma. 2004 Mar;21(3):307-16
references.pmid: 15115605
references.citation: Neurotherapeutics. 2010 Oct;7(4):366-77
references.pmid: 20880501
references.citation: Exp Neurol. 2007 Oct;207(2):227-37
references.pmid: 17698063
references.citation: Neurosci Biobehav Rev. 2009 Mar;33(3):355-66
references.pmid: 18996146
references.citation: J Neurocytol. 1976 Feb;5(1):63-84
references.pmid: 1249593
references.citation: J Neurosci. 2002 Feb 1;22(3):1155-64
references.pmid: 11826144
references.citation: Science. 2002 Mar 22;295(5563):2282-5
references.pmid: 11910117
references.citation: Diabetes. 2005 May;54(5):1559-65
references.pmid: 15855346
references.citation: Science. 2011 Sep 9;333(6048):1456-8
references.pmid: 21778362
references.citation: Immunology. 1994 Sep;83(1):140-7
references.pmid: 7821959
references.citation: J Neuroinflammation. 2008 May 13;5:15
references.pmid: 18477398
references.citation: Pediatr Crit Care Med. 2001 Jul;2(3):260-264
references.pmid: 12793952
references.citation: J Neurotrauma. 2007 Oct;24(10):1596-608
references.pmid: 17970623
references.citation: Brain Behav Immun. 2014 Nov;42:147-56
references.pmid: 24994592
references.citation: J Neuropathol Exp Neurol. 2014 Apr;73(4):345-61
references.pmid: 24607965
references.citation: Exp Neurol. 2007 Mar;204(1):220-33
references.pmid: 17188268
references.citation: Exp Neurol. 2002 Jul;176(1):105-16
references.pmid: 12093087
references.citation: J Neurotrauma. 2014 Oct 1;31(19):1647-63
references.pmid: 24797413
references.citation: J Neurotrauma. 2011 Oct;28(10):2135-43
references.pmid: 21770756
references.citation: Pediatr Res. 1996 Jan;39(1):39-47
references.pmid: 8825384
references.citation: Brain Res Dev Brain Res. 1995 Feb 16;84(2):245-52
references.pmid: 7743644
references.citation: J Neurotrauma. 2012 May 1;29(7):1410-25
references.pmid: 22260446
references.citation: Pediatrics. 2009 May;123(5):1409-11
references.pmid: 19403508
references.citation: CNS Neurol Disord Drug Targets. 2013 May 1;12(3):338-49
references.pmid: 23469850
references.citation: Int J Antimicrob Agents. 2002 Apr;19(4):261-8
references.pmid: 11978497
references.citation: J Neuroimmunol. 2003 Nov;144(1-2):61-7
references.pmid: 14597099
references.citation: Curr Probl Pediatr Adolesc Health Care. 2006 Oct;36(9):318-31
references.pmid: 16996420
references.citation: Brain Res. 2009 Sep 29;1291:122-32
references.pmid: 19631631
references.citation: J Neurotrauma. 2004 Sep;21(9):1123-30
references.pmid: 15453983
references.citation: J Cereb Blood Flow Metab. 2005 Sep;25(9):1138-49
references.pmid: 15874975
references.citation: NeuroRx. 2006 Apr;3(2):143-53
references.pmid: 16554253
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10483-7
references.pmid: 12930891
references.citation: Pediatr Neurosurg. 1998 Aug;29(2):77-85
references.pmid: 9792961
references.citation: J Exp Med. 2005 Feb 21;201(4):647-57
references.pmid: 15728241
references.citation: Dev Med Child Neurol. 1995 Nov;37(11):943-56
references.pmid: 8566455
references.citation: J Neurotrauma. 2011 Apr;28(4):547-63
references.pmid: 21299360
references.citation: Childs Nerv Syst. 2000 Jan;16(1):25-33; discussion 34
references.pmid: 10672426
references.citation: J Neurosci Res. 2009 Feb 15;87(3):599-608
references.pmid: 18831005
references.citation: Brain Pathol. 2002 Jul;12(3):320-8
references.pmid: 12146800
references.citation: Acta Paediatr. 2007 Aug;96(8):1159-63
references.pmid: 17578493
references.citation: Int J Dev Neurosci. 2008 Aug;26(5):477-85
references.pmid: 18387771
references.citation: Ross Fiziol Zh Im I M Sechenova. 2012 Jun;98(6):782-92
references.pmid: 23013016
references.citation: Front Neurol. 2012 Jul 16;3:111
references.pmid: 22811676
references.citation: Arch Neurol. 2010 Dec;67(12):1442-8
references.pmid: 20697034
references.citation: J Cereb Blood Flow Metab. 2010 Jan;30(1):119-29
references.pmid: 19756023
references.citation: Neurosurgery. 2001 Jun;48(6):1393-9; discussion 1399-401
references.pmid: 11383749
references.citation: Exp Neurol. 2004 Sep;189(1):58-65
references.pmid: 15296836
references.citation: J Clin Neurosci. 2012 Aug;19(8):1159-64
references.pmid: 22705132
references.citation: Brain Res. 2009 Mar 31;1263:174-82
references.pmid: 19368848
references.citation: J Neurosci. 2011 Sep 7;31(36):12992-3001
references.pmid: 21900578
references.citation: Ann Neurol. 2002 Jul;52(1):54-61
references.pmid: 12112047
references.citation: Pharmacotherapy. 2006 Apr;26(4):515-21
references.pmid: 16553511
references.citation: Exp Neurol. 2008 Sep;213(1):84-92
references.pmid: 18599043
references.citation: Behav Brain Res. 2003 Mar 18;140(1-2):107-18
references.pmid: 12644284
references.citation: Cell Death Dis. 2013 Mar 07;4:e525
references.pmid: 23470532
references.citation: Neuroscience. 2011 May 19;182:184-92
references.pmid: 21440046
references.citation: Behav Brain Res. 2002 Nov 15;136(2):329-37
references.pmid: 12429394
references.citation: Arch Pediatr Adolesc Med. 2000 Jan;154(1):11-5
references.pmid: 10632244
references.citation: Am J Pathol. 2010 Mar;176(3):1193-202
references.pmid: 20110416
references.citation: Brain Behav Immun. 2013 Oct;33:15-23
references.pmid: 23747799
references.citation: Pediatrics. 2005 Aug;116(2):e174-85
references.pmid: 16061571
references.citation: J Neurotrauma. 2007 Jan;24(1):15-27
references.pmid: 17263667
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3071-6
references.pmid: 14981254
references.citation: J Neurochem. 2011 Dec;119(5):901-8
references.pmid: 21951310
references.citation: J Neurotrauma. 2009 Jul;26(7):1111-21
references.pmid: 19275468
references.citation: Dev Neurosci. 2010;32(5-6):510-8
references.pmid: 20829578
references.citation: J Neurochem. 2006 Jun;97(5):1314-26
references.pmid: 16638021
references.citation: Neurosci Lett. 2012 Mar 9;511(2):110-5
references.pmid: 22314279
references.citation: Neuropathol Appl Neurobiol. 2008 Aug;34(4):379-93
references.pmid: 18221261
references.citation: Eur J Neurosci. 2006 Jul;24(2):341-50
references.pmid: 16836639
references.citation: Neuroscience. 2006;137(2):425-35
references.pmid: 16289838
references.citation: J Neuroimmunol. 2007 Mar;184(1-2):92-9
references.pmid: 17239445
references.citation: J Neuroinflammation. 2008 Aug 11;5:34
references.pmid: 18694515
references.citation: JAMA. 1999 Feb 17;281(7):621-6
references.pmid: 10029123
references.citation: Pediatr Neurosurg. 1996 Jun;24(6):292-8
references.pmid: 8988494
references.citation: Pediatrics. 2009 Dec;124(6):1587-94
references.pmid: 19948629
references.citation: Brain Res. 1990 Sep 3;526(2):249-58
references.pmid: 2257484
references.citation: Neurotherapeutics. 2010 Jan;7(1):22-30
references.pmid: 20129494
references.citation: J Neurotrauma. 2007 Sep;24(9):1460-74
references.pmid: 17892408