title: Erythropoietin improved cognitive function and decreased hippocampal caspase activity in rat pups after traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model.
  
  
  OBJECTIVE
  We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI).
  
  
  METHODS
  EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2.
  
  
  RESULTS
  EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury.
authors: 1 Department of Pediatrics, Division of Critical Care, University of Utah , Salt Lake City, Utah.
authors: Michelle E
authors: ME
authors: Schober
authors: Daniela F
authors: DF
authors: Requena
authors: Benjamin
authors: B
authors: Block
authors: Lizeth J
authors: LJ
authors: Davis
authors: Christopher
authors: C
authors: Rodesch
authors: T Charles
authors: TC
authors: Casper
authors: Sandra E
authors: SE
authors: Juul
authors: Raymond P
authors: RP
authors: Kesner
authors: Robert H
authors: RH
authors: Lane
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology*; D020169:Caspases / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D006400:Hematocrit; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D021641:Recognition, Psychology / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D020169:Caspases
references: Pediatr Res. 2007 Jun;61(6):671-5
references: 17426655
references: Pediatr Dev Pathol. 1999 Mar-Apr;2(2):148-58
references: 9949221
references: Cell Cycle. 2004 Feb;3(2):205-11
references: 14712090
references: Neuropsychology. 2002 Oct;16(4):514-23
references: 12382990
references: Dev Neuropsychol. 2007;32(2):683-701
references: 17931125
references: Pathophysiology. 2013 Feb;20(1):31-8
references: 22421507
references: J Neurotrauma. 2008 Feb;25(2):112-23
references: 18260794
references: IEEE Trans Biomed Eng. 2013 Jan;60(1):90-6
references: 23070292
references: J Neurosurg. 2007 Aug;107(2):392-7
references: 17695395
references: Brain Res. 2009 Sep 15;1289:96-105
references: 19615349
references: Neurol India. 2009 Nov-Dec;57(6):722-8
references: 20139499
references: Mol Med. 2012 May 09;18:628-35
references: 22396019
references: Neurosci Lett. 2007 Oct 2;425(3):177-82
references: 17825990
references: Neurobiol Dis. 2004 Mar;15(2):177-87
references: 15006687
references: Eur J Clin Pharmacol. 2005 May;61(3):189-95
references: 15776276
references: Exp Neurol. 2012 May;235(1):336-44
references: 22414310
references: Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2425-31
references: 11709408
references: Crit Rev Oncol Hematol. 2007 Nov;64(2):159-71
references: 17482474
references: Cell Death Differ. 2010 Jul;17(7):1104-14
references: 19960023
references: Biol Neonate. 2001;79(3-4):228-35
references: 11275657
references: Ann Neurol. 1999 Jun;45(6):724-35
references: 10360764
references: Glia. 2006 Mar;53(4):360-5
references: 16288465
references: Dev Neurosci. 2009;31(5):403-11
references: 19672069
references: Pediatrics. 2012 Oct;130(4):683-91
references: 23008465
references: J Am Acad Child Adolesc Psychiatry. 2005 Jun;44(6):574-84
references: 15908840
references: J Neurotrauma. 2010 Jan;27(1):205-15
references: 19715391
references: J Neurotrauma. 2010 Nov;27(11):2011-20
references: 20822461
references: J Neurosurg. 2008 Sep;109(3):510-21
references: 18759585
references: Biol Mood Anxiety Disord. 2012 Sep 12;2:15
references: 22967286
references: Eur J Neurosci. 2002 Aug;16(4):584-92
references: 12270034
references: Learn Mem. 2009 Dec 22;17(1):5-11
references: 20028732
references: Brain Res. 2011 Mar 10;1378:54-65
references: 21241681
references: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2508-13
references: 10051673
references: Circ Res. 1965 Jul;17:30-8
references: 14302550
references: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3717-20
references: 7731971
references: J Korean Med Sci. 2008 Jun;23(3):484-91
references: 18583887
references: Neuropharmacology. 2013 Apr;67:8-15
references: 23142737
references: Pediatrics. 2008 Aug;122(2):383-91
references: 18676557
references: J Neurotrauma. 2008 Oct;25(10):1179-85
references: 18842103
references: Trends Pharmacol Sci. 2004 Nov;25(11):577-83
references: 15491780
references: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4635-40
references: 9539790
references: Surg Neurol. 2009 May;71(5):527-31; discussion 531
references: 18789503
references: Exp Toxicol Pathol. 2004 Oct;56(1-2):83-9
references: 15581279
references: J Head Trauma Rehabil. 2006 Sep-Oct;21(5):375-8
references: 16983222
references: J Cereb Blood Flow Metab. 2007 Jul;27(7):1369-76
references: 17264861
references: Brain Res. 2012 May 3;1452:18-28
references: 22444273
references: Int J Dev Neurosci. 2012 May;30(3):217-24
references: 22100364
references: Dev Neurosci. 2007;29(4-5):321-30
references: 17762200
references: Biol Neonate. 2004;85(2):138-44
references: 14639039
references: J Pathol. 2011 May;224(1):101-9
references: 21404277
references: Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2413-21
references: 21984540
references: J Biol Chem. 1998 Feb 20;273(8):4523-9
references: 9468507
references: Br J Pharmacol. 2003 Mar;138(6):1107-18
references: 12684267
references: J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):401-8
references: 15716536
references: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10526-31
references: 10984541
references: Br J Pharmacol. 2007 Aug;151(8):1377-84
references: 17603558
references: Eur J Neurosci. 2012 Oct;36(7):2941-8
references: 22845676
references: Acta Neurochir Suppl. 2008;105:105-12
references: 19066093
references: Brain Res. 2007 Nov 28;1182:99-105
references: 17935704
references: Pediatr Res. 2005 May;57(5 Pt 2):110R-117R
references: 15817504
references: J Head Trauma Rehabil. 2005 May-Jun;20(3):229-38
references: 15908823
references: Pediatrics. 2006 Apr;117(4):e663-74
references: 16533894
references: Environ Health Perspect. 2000 Jun;108 Suppl 3:511-33
references: 10852851
references: Neurosci Bull. 2008 Apr;24(2):89-95
references: 18369388
references: Cogn Process. 2012 May;13(2):93-110
references: 22160349
references: Child Neuropsychol. 2007 May;13(3):240-61
references: 17453832
references: FASEB J. 2005 Oct;19(12):1701-3
references: 16099948
references: Dev Psychobiol. 2009 Dec;51(8):672-8
references: 19739136
references: Pediatrics. 2009 Jan;123(1):199-206
references: 19117883
references: Glia. 2009 May;57(7):693-702
references: 18985736
references: Pediatrics. 2005 Dec;116(6):1374-82
references: 16322161
references: Dev Neurosci. 2010;32(5-6):480-7
references: 21228558
references: Cell Death Differ. 2003 Mar;10(3):365-70
references: 12700636
references: Eur J Neurol. 2008 Feb;15(2):140-9
references: 18093155
references: Neuroscience. 2007 Aug 10;148(1):250-65
references: 17614212