Early and sustained increase in the expression of hippocampal IGF-1, but not EPO, in a developmental rodent model of traumatic brain injury.
Pediatric traumatic brain injury (pTBI) is the leading cause of traumatic death and disability in children in the United States. Impaired learning and memory in these young survivors imposes a heavy toll on society. In adult TBI (aTBI) models, cognitive outcome improved after administration of erythropoietin (EPO) or insulin-like growth factor-1 (IGF-1). Little is known about the production of these agents in the hippocampus, a brain region critical for learning and memory, after pTBI. Our objective was to describe hippocampal expression of EPO and IGF-1, together with their receptors (EPOR and IGF-1R, respectively), over time after pTBI in 17-day-old rats. We used the controlled cortical impact (CCI) model and measured hippocampal mRNA levels of EPO, IGF-1, EPOR, IGF-1R, and markers of caspase-dependent apoptosis (bcl2, bax, and p53) at post-injury days (PID) 1, 2, 3, 7, and 14. CCI rats performed poorly on Morris water maze testing of spatial working memory, a hippocampally-based cognitive function. Apoptotic markers were present early and persisted for the duration of the study. EPO in our pTBI model increased much later (PID7) than in aTBI models (12 h), while EPOR and IGF-1 increased at PID1 and PID2, respectively, similar to data from aTBI models. Our data indicate that EPO expression showed a delayed upregulation post-pTBI, while EPOR increased early. We speculate that administration of EPO in the first 1-2 days after pTBI would increase hippocampal neuronal survival and function.
Schober
Michelle E
ME
Department of Pediatrics, Division of Critical Care, University of Utah, Salt Lake City, Utah 84158, USA. michelle.schober@hsc.utah.edu
Block
Benjamin
B
Beachy
Joanna C
JC
Statler
Kimberly D
KD
Giza
Christopher C
CC
Lane
Robert H
RH
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000523:psychology; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I
Neuroscience. 1994 Nov;63(2):579-89
7891866
Acta Neurochir Suppl. 1998;71:104-6
9779157
Exp Neurol. 2008 Sep;213(1):84-92
18599043
Brain Res. 2006 Aug 30;1107(1):70-81
16822489
J Am Acad Child Adolesc Psychiatry. 2005 Jun;44(6):574-84
15908840
Ann Neurol. 2009 May;65(5):540-9
19475669
J Neurosci Res. 2007 Jun;85(8):1618-27
17455296
J Neurotrauma. 2010 Jan;27(1):95-107
19751099
J Neurosci Res. 2002 Mar 1;67(5):646-63
11891777
Pediatr Res. 2007 Sep;62(3):271-6
17622965
Endocrinology. 1991 Feb;128(2):923-8
1989870
Biol Neonate. 2001;79(3-4):228-35
11275657
Ann Neurol. 1999 Jun;45(6):724-35
10360764
Crit Care. 2005 Feb;9(1):66-75
15693986
J Neurotrauma. 2009 Jan;26(1):121-9
19119914
Gen Comp Endocrinol. 2006 Jun;147(2):196-205
16500651
Early Hum Dev. 1979 Mar;3(1):79-83
118862
Childs Nerv Syst. 2007 Oct;23(10):1171-9
17457592
J Neurosci Methods. 1991 Oct;39(3):253-62
1787745
Brain Res Brain Res Protoc. 1998 Sep;3(1):1-6
9767074
Cell Cycle. 2004 Feb;3(2):205-11
14712090
Endocrinology. 1997 Jul;138(7):3024-34
9202248
Exp Toxicol Pathol. 2004 Oct;56(1-2):83-9
15581279
J Head Trauma Rehabil. 2006 Sep-Oct;21(5):375-8
16983222
J Comp Neurol. 2009 Jun 1;514(4):403-14
19330822
Neuropsychology. 2002 Oct;16(4):514-23
12382990
Brain Res. 2001 Aug 17;911(1):96-100
11489449
Endocr Rev. 2005 Dec;26(7):916-43
16131630
Brain Res Mol Brain Res. 1996 Jun;38(2):285-93
8793117
J Neurosci Res. 2008 Aug 1;86(10):2258-70
18381764
Neuroscience. 2007 Aug 24;148(2):359-70
17681695
Exp Gerontol. 2006 Nov;41(11):1201-5
16978820
Neurosci Lett. 2007 Jun 13;420(2):133-7
17531385
Exp Neurol. 1997 Oct;147(2):418-27
9344566
J Neurochem. 2007 Jun;101(5):1248-57
17403141
J Neurotrauma. 2005 Sep;22(9):1011-7
16156716
Pediatr Res. 2005 May;57(5 Pt 2):110R-117R
15817504
Mech Ageing Dev. 2005 Jun-Jul;126(6-7):692-704
15888324
J Neurotrauma. 2009 Sep;26(9):1557-66
19203226
J Head Trauma Rehabil. 2005 May-Jun;20(3):229-38
15908823
Brain Res Mol Brain Res. 1998 Jun 1;57(1):92-6
9630538
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9855-60
15210945
Environ Health Perspect. 2000 Jun;108 Suppl 3:511-33
10852851
BMC Genomics. 2007 Apr 04;8:94
17408481
J Neurotrauma. 2010 Mar;27(3):647-51
19929186
Pediatrics. 2005 Dec;116(6):1374-82
16322161
Eur J Neurol. 2008 Feb;15(2):140-9
18093155
Am J Pathol. 1995 Dec;147(6):1575-83
7495282