title: The effect of hypothermia therapy on cortical laminar disruption following ischemic injury in neonatal mice.
abstract: Hypothermia has been proposed as a treatment for reducing neuronal damage in the brain induced by hypoxic ischemia. In the developing brain, hypoxic ischemia-induced injury may give rise to cerebral palsy (CP). However, it is unknown whether hypothermia might affect the development of CP. The purpose of this study was to investigate whether hypothermia would have a protective effect on the brains of immature, 3-day old (P3) mice after a challenge of cerebral ischemia. Cerebral ischemia was induced in P3 mice with a right common carotid artery ligation followed by hypoxia (6% O2, 37°C) for 30 min. Immediately after hypoxic ischemia, mice were exposed to hypothermia (32°C) or normothermia (37°C) for 24 h. At 4 weeks of age, mouse motor development was tested in a behavioral test. Mice were sacrificed at P4, P7, and 5 weeks to examine brain morphology. The laminar structure of the cortex was examined with immunohistochemistry (Cux1/Ctip2); the number of neurons was counted; and the expression of myelin basic protein (MBP) was determined. The hypothermia treatment was associated with improved neurological outcomes in the behavioral test. In the normothermia group, histological analyses indicated reduced numbers of neurons, reduced cortical laminar thickness in the deep, ischemic cortical layers, and significant reduction in MBP expression in the ischemic cortex compared to the contralateral cortex. In the hypothermia group, no reductions were noted in deep cortical layer thickness and in MBP expression in the ischemic cortex compared to the contralateral cortex. At 24 h after the hypothermia treatment prevented the neuronal cell death that had predominantly occurred in the ischemic cortical deep layers with normothermia treatment. Our findings may provide a preclinical basis for testing hypothermal therapies in patients with CP induced by hypoxic ischemia in the preterm period.
authors.affiliation: Department of Systems Neuroscience, Graduate School of Medicine Yamaguchi University, Ube, Japan. h-kida@yamaguchi-u.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kida
authors.forename: Sadahiro
authors.initials: S
authors.lastname: Nomura
authors.forename: Mizuya
authors.initials: M
authors.lastname: Shinoyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Ideguchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D002452:Cell Count; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007150:Immunohistochemistry; D051379:Mice; D009043:Motor Activity; D004676:Myelin Basic Protein; D009474:Neurons / Q000473:pathology
chemical_list: D004676:Myelin Basic Protein
references.citation: J Neurosci. 1987 Feb;7(2):357-68
references.pmid: 2880937
references.citation: Dev Neurosci. 2011;33(3-4):320-9
references.pmid: 21912083
references.citation: Pediatrics. 2003 Jul;112(1 Pt 1):176-80
references.pmid: 12837883
references.citation: Ann Neurol. 1981 Feb;9(2):131-41
references.pmid: 7235629
references.citation: J Cereb Blood Flow Metab. 2012 Jun;32(6):978-82
references.pmid: 22434066
references.citation: Birth Defects Res C Embryo Today. 2007 Sep;81(3):163-76
references.pmid: 17963273
references.citation: Pediatrics. 2007 Sep;120(3):584-93
references.pmid: 17766532
references.citation: Brain Res. 2001 Aug 10;910(1-2):187-91
references.pmid: 11489270
references.citation: J Neuropathol Exp Neurol. 2002 Feb;61(2):197-211
references.pmid: 11853021
references.citation: J Comp Neurol. 1970 Jan;138(1):31-47
references.pmid: 5412719
references.citation: Nat Rev Neurosci. 2002 Jun;3(6):423-32
references.pmid: 12042877
references.citation: Clin Neurophysiol. 2012 Sep;123(9):1708-13
references.pmid: 22459055
references.citation: Int J Dev Neurosci. 2001 Apr;19(2):197-208
references.pmid: 11255033
references.citation: J Cereb Blood Flow Metab. 2000 Aug;20(8):1149-65
references.pmid: 10950376
references.citation: Pediatr Res. 2012 May;71(5):566-72
references.pmid: 22322383
references.citation: Trends Pharmacol Sci. 2008 Nov;29(11):550-7
references.pmid: 18805596
references.citation: N Engl J Med. 2009 Oct 1;361(14):1349-58
references.pmid: 19797281
references.citation: Brain Res. 2013 Feb 25;1497:53-60
references.pmid: 23268352
references.citation: Neuroscience. 2001;105(1):7-17
references.pmid: 11483296
references.citation: N Engl J Med. 2005 Oct 13;353(15):1574-84
references.pmid: 16221780
references.citation: Neurosci Lett. 1989 Jul 3;101(3):299-304
references.pmid: 2771174
references.citation: Curr Opin Cell Biol. 2004 Dec;16(6):663-9
references.pmid: 15530778
references.citation: J Neurosci. 2001 Feb 15;21(4):1302-12
references.pmid: 11160401
references.citation: Pediatr Neurol. 2009 Mar;40(3):156-67
references.pmid: 19218028
references.citation: Anesthesiology. 1996 Sep;85(3):600-7
references.pmid: 8853091
references.citation: J Neurosci. 2000 Nov 1;20(21):7994-8004
references.pmid: 11050120
references.citation: Pediatr Res. 2002 Mar;51(3):354-60
references.pmid: 11861942
references.citation: Pediatr Res. 2001 Nov;50(5):553-62
references.pmid: 11641446
references.citation: Brain Res Bull. 2009 Aug 14;79(6):351-7
references.pmid: 19406216
references.citation: Exp Neurol. 2003 Jun;181(2):231-40
references.pmid: 12781996
references.citation: Anat Embryol (Berl). 1995 Feb;191(2):89-100
references.pmid: 7726396
references.citation: Pediatr Res. 2003 Aug;54(2):263-9
references.pmid: 12736386
references.citation: Brain Res. 2009 Dec 8;1301:100-9
references.pmid: 19747899
references.citation: Lancet. 2005 Feb 19-25;365(9460):663-70
references.pmid: 15721471
references.citation: Brain Dev. 2005 Oct;27(7):517-26
references.pmid: 15899566
references.citation: Nat Rev Neurosci. 2012 Feb 22;13(4):267-78
references.pmid: 22353781
references.citation: J Neurosci. 2003 Apr 15;23(8):3308-15
references.pmid: 12716938
references.citation: Am J Anat. 1981 Mar;160(3):247-55
references.pmid: 6164286
references.citation: Brain Res. 2003 Dec 12;993(1-2):101-10
references.pmid: 14642835
references.citation: N Engl J Med. 2012 May 31;366(22):2085-92
references.pmid: 22646631
references.citation: Pediatr Res. 2002 Jan;51(1):25-33
references.pmid: 11756636
references.citation: BMC Pregnancy Childbirth. 2003 Dec 23;3(1):8
references.pmid: 14693037
references.citation: Pediatr Res. 2010 Oct;68(4):303-8
references.pmid: 20606598
references.citation: Pediatr Res. 2005 Jun;57(6):865-72
references.pmid: 15774844
references.citation: Brain Res. 2006 Mar 10;1077(1):187-99
references.pmid: 16483552