title: Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.
abstract: Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients.
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Chengrui
authors.initials: C
authors.lastname: An
authors.affiliation: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Suenaga
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA. Electronic address: chenj2@upmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: yqgao@shmu.edu.cn.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001930:Brain Injuries / Q000150:complications* / Q000628:therapy*; D016923:Cell Death; D003072:Cognition Disorders / Q000209:etiology; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000150:complications / Q000209:etiology*; D006801:Humans; D007511:Ischemia / Q000150:complications* / Q000628:therapy*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: Cerebral ischemia; Demyelination; Oligodendrocyte; Remyelination; Traumatic brain injury
references.citation: BMC Neurol. 2001 Dec 18;1:3
references.pmid: 11504565
references.citation: Mol Cell Neurosci. 1996 May;7(5):354-70
references.pmid: 8812062
references.citation: Glia. 2013 Mar;61(3):383-93
references.pmid: 23281060
references.citation: Transl Stroke Res. 2013 Dec;4(6):618-34
references.pmid: 24323416
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6832-6
references.pmid: 19342494
references.citation: Annu Rev Neurosci. 2008;31:535-61
references.pmid: 18558866
references.citation: Nat Rev Neurosci. 2010 Apr;11(4):275-83
references.pmid: 20216548
references.citation: Stroke. 2011 Nov;42(11):3294-6
references.pmid: 21940976
references.citation: J Neurosci. 2012 Sep 12;32(37):12854-61
references.pmid: 22973009
references.citation: Brain. 2008 Jun;131(Pt 6):1464-77
references.pmid: 18490361
references.citation: J Cereb Blood Flow Metab. 2011 Apr;31(4):1155-69
references.pmid: 21139628
references.citation: Prog Neurobiol. 2014 Aug-Sep;119-120:60-84
references.pmid: 24923657
references.citation: J Neuroimmunol. 2014 Jan 15;266(1-2):12-23
references.pmid: 24275061
references.citation: Brain Res. 2011 May 25;1392:93-100
references.pmid: 21447326
references.citation: J Neuroinflammation. 2009;6:4
references.pmid: 19159481
references.citation: J Neurochem. 2008 Oct;107(1):1-19
references.pmid: 18643793
references.citation: Science. 2014 Oct 17;346(6207):318-22
references.pmid: 25324381
references.citation: Glia. 2014 Feb;62(2):272-83
references.pmid: 24310780
references.citation: CNS Drugs. 2013 Jul;27(7):493-503
references.pmid: 23681979
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2853-8
references.pmid: 25691750
references.citation: Neurobiol Aging. 2010 Jul;31(7):1122-31
references.pmid: 18801597
references.citation: Mol Cell Biol. 2004 Aug;24(15):6592-607
references.pmid: 15254227
references.citation: Cell. 2003 Feb 21;112(4):481-90
references.pmid: 12600312
references.citation: J Neuropathol Exp Neurol. 2009 Jun;68(6):595-604
references.pmid: 19458544
references.citation: Neurology. 2000 Oct 24;55(8):1158-66
references.pmid: 11071494
references.citation: Science. 2010 Nov 5;330(6005):779-82
references.pmid: 21051629
references.citation: Nat Neurosci. 2013 Sep;16(9):1211-8
references.pmid: 23872599
references.citation: J Biol Chem. 2012 Jun 22;287(26):22184-95
references.pmid: 22514275
references.citation: Nature. 2006 Feb 23;439(7079):988-92
references.pmid: 16372019
references.citation: Brain Pathol. 2008 Jul;18(3):387-400
references.pmid: 18371179
references.citation: Nat Rev Mol Cell Biol. 2014 Jan;15(1):49-63
references.pmid: 24355989
references.citation: Science. 2014 Oct 17;346(6207):298-9
references.pmid: 25324370
references.citation: Nat Neurosci. 2010 Mar;13(3):310-8
references.pmid: 20098419
references.citation: Nature. 2005 Dec 22;438(7071):1167-71
references.pmid: 16372012
references.citation: Exp Neurol. 2011 Sep;231(1):19-29
references.pmid: 21596037
references.citation: Rev Neurosci. 2013;24(1):71-88
references.pmid: 23152401
references.citation: Nat Neurosci. 2009 Nov;12(11):1370-1
references.pmid: 19820707
references.citation: Prog Neurobiol. 2014 Apr;115:6-24
references.pmid: 24374228
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: Stroke. 1996 Sep;27(9):1641-6; discussion 1647
references.pmid: 8784142
references.citation: J Neurosci Res. 2005 Apr 15;80(2):226-34
references.pmid: 15765524
references.citation: Development. 2013 Aug;140(15):3107-17
references.pmid: 23824572
references.citation: J Neurosci. 2011 Jan 12;31(2):784-91
references.pmid: 21228187
references.citation: Mult Scler. 2012 Aug;18(8):1058-67
references.pmid: 22723572
references.citation: Front Cell Neurosci. 2013 Dec 26;7:277
references.pmid: 24421756
references.citation: Brain Res. 1995 Nov 6;698(1-2):86-94
references.pmid: 8581507
references.citation: J Neurosci. 2006 Oct 25;26(43):10984-91
references.pmid: 17065440
references.citation: Neuropathol Appl Neurobiol. 2008 Dec;34(6):577-89
references.pmid: 19076696
references.citation: Ann Neurol. 2012 Nov;72(5):648-72
references.pmid: 23280789
references.citation: J Cell Biol. 2005 May 23;169(4):603-12
references.pmid: 15911877
references.citation: Front Biosci (Elite Ed). 2012;4:1926-36
references.pmid: 22202008
references.citation: J Neurosci. 2005 Aug 31;25(35):7924-33
references.pmid: 16135749
references.citation: Transl Stroke Res. 2014 Feb;5(1):136-44
references.pmid: 24323707
references.citation: J Neurosci. 2001 Jun 15;21(12):4237-48
references.pmid: 11404409
references.citation: J Neurochem. 2011 Oct;119(1):176-88
references.pmid: 21848846
references.citation: J Cell Biol. 2009 Jul 13;186(1):113-28
references.pmid: 19596850
references.citation: J Neurosci. 2006 Nov 22;26(47):12174-85
references.pmid: 17122042
references.citation: Ann Neurol. 2011 Oct;70(4):525-9
references.pmid: 22028217
references.citation: Stroke. 2012 Nov;43(11):3063-70
references.pmid: 22933588
references.citation: Nat Rev Neurol. 2013 Apr;9(4):231-6
references.pmid: 23443846
references.citation: Ann Neurol. 2009 Mar;65(3):304-15
references.pmid: 19334062
references.citation: Neurobiol Dis. 2005 Jun-Jul;19(1-2):171-82
references.pmid: 15837572
references.citation: Neuron. 2013 Mar 6;77(5):873-85
references.pmid: 23473318
references.citation: Nat Rev Neurol. 2015 Jan;11(1):56-64
references.pmid: 25385337
references.citation: Eur J Neurosci. 2007 Feb;25(3):761-71
references.pmid: 17298600
references.citation: Transl Stroke Res. 2013 Feb;4(1):104-13
references.pmid: 24323191
references.citation: Neuroscience. 1997 Apr;77(3):849-61
references.pmid: 9070757
references.citation: Nature. 2014 Feb 13;506(7487):230-4
references.pmid: 24390343
references.citation: Biochim Biophys Acta. 2011 Feb;1812(2):184-93
references.pmid: 20887785
references.citation: J Neurosci. 2011 Mar 9;31(10):3719-28
references.pmid: 21389227
references.citation: J Neurosci. 2009 Oct 28;29(43):13435-44
references.pmid: 19864556
references.citation: Cytokine. 1997 Oct;9(10):734-9
references.pmid: 9344504
references.citation: J Immunol. 2005 Nov 1;175(9):5875-84
references.pmid: 16237080
references.citation: J Neuroinflammation. 2011;8:108
references.pmid: 21871134
references.citation: Nat Genet. 2003 Mar;33(3):366-74
references.pmid: 12590258
references.citation: Science. 2011 Sep 16;333(6049):1647-51
references.pmid: 21817014
references.citation: J Cereb Blood Flow Metab. 2013 Dec;33(12):1864-74
references.pmid: 23942366
references.citation: Glia. 2008 Jan 15;56(2):233-40
references.pmid: 18046734
references.citation: Prog Neurobiol. 2009 Apr;87(4):264-80
references.pmid: 19428957
references.citation: J Neuroimmunol. 2005 Jan;158(1-2):58-66
references.pmid: 15589038
references.citation: J Neurotrauma. 2011 Jun;28(6):1089-100
references.pmid: 21309692
references.citation: Cell Death Differ. 2014 Aug;21(8):1198-208
references.pmid: 24658399
references.citation: Trends Cell Biol. 2013 Dec;23(12):644-51
references.pmid: 23988427
references.citation: J Neurochem. 2011 Jan;116(1):53-66
references.pmid: 21044081
references.citation: F1000 Biol Rep. 2010 Aug 09;2:57
references.pmid: 21173873
references.citation: Nature. 2010 Nov 11;468(7321):244-52
references.pmid: 21068833
references.citation: Nat Rev Neurosci. 2008 Nov;9(11):839-55
references.pmid: 18931697
references.citation: Biochim Biophys Acta. 2012 Mar;1822(3):416-22
references.pmid: 21803153
references.citation: J Anat. 2007 Jun;210(6):693-702
references.pmid: 17504270
references.citation: Glia. 2006 Jan 15;53(2):212-24
references.pmid: 16206168
references.citation: Neurology. 2000 Mar 28;54(6):1316-23
references.pmid: 10746604
references.citation: Stroke. 2005 Dec;36(12):2742-4
references.pmid: 16269640
references.citation: Lancet Neurol. 2009 Mar;8(3):280-91
references.pmid: 19233038
references.citation: Nat Neurosci. 2007 Mar;10(3):321-30
references.pmid: 17293857
references.citation: Ann Neurol. 2008 Apr;63(4):520-30
references.pmid: 18393269
references.citation: J Cell Biol. 1999 Dec 13;147(6):1123-8
references.pmid: 10601327
references.citation: J Neurosci. 2007 Dec 19;27(51):13949-57
references.pmid: 18094232
references.citation: Stroke. 2013 Apr;44(4):1204-11
references.pmid: 23212168
references.citation: Prog Neurobiol. 2014 Apr;115:157-88
references.pmid: 24361499
references.citation: Brain. 2011 Apr;134(Pt 4):1156-67
references.pmid: 21421691
references.citation: Stroke. 2007 Oct;38(10):2826-32
references.pmid: 17761909
references.citation: Cell Death Dis. 2010;1:e54
references.pmid: 21364659
references.citation: Stroke. 2013 Dec;44(12):3516-21
references.pmid: 24072001
references.citation: Exp Neurol. 2008 Apr;210(2):585-91
references.pmid: 18222425
references.citation: PLoS One. 2012;7(5):e37589
references.pmid: 22629425
references.citation: Nat Neurosci. 2008 Dec;11(12):1392-401
references.pmid: 18849983
references.citation: Nature. 2012 Jul 26;487(7408):443-8
references.pmid: 22801498
references.citation: J Neurosci. 2006 Jul 26;26(30):7907-18
references.pmid: 16870736
references.citation: Transl Stroke Res. 2014 Feb;5(1):156-62
references.pmid: 24399572
references.citation: J Neuroinflammation. 2014;11:215
references.pmid: 25540015
references.citation: Hum Brain Mapp. 2011 Jan;32(1):10-21
references.pmid: 20235096
references.citation: Front Endocrinol (Lausanne). 2013 May 13;4:54
references.pmid: 23717302
references.citation: Glia. 2013 May;61(5):750-64
references.pmid: 23440871
references.citation: Neuroscience. 2008 Mar 27;152(3):601-8
references.pmid: 18313228
references.citation: Nat Neurosci. 2005 Sep;8(9):1148-50
references.pmid: 16116456
references.citation: Front Neurosci. 2014 Jun 12;8:145
references.pmid: 24971048
references.citation: PLoS One. 2013;8(11):e80975
references.pmid: 24260524
references.citation: Cell Stem Cell. 2008 Jun 5;2(6):553-65
references.pmid: 18522848
references.citation: AJNR Am J Neuroradiol. 2013 Nov-Dec;34(11):2064-74
references.pmid: 23306011
references.citation: Nature. 2005 Dec 22;438(7071):1162-6
references.pmid: 16372011
references.citation: Neurosci Biobehav Rev. 1997 Mar;21(2):151-66
references.pmid: 9062938
references.citation: Alzheimers Dement. 2010 Sep;6(5):394-403
references.pmid: 20713315
references.citation: Cerebrovasc Dis. 2002;13 Suppl 2:53-7
references.pmid: 11901244
references.citation: J Neurosci. 1998 Jul 15;18(14):5354-65
references.pmid: 9651218
references.citation: J Neurosci. 2008 May 14;28(20):5321-30
references.pmid: 18480288
references.citation: Ann Neurol. 2003 May;53(5):588-95
references.pmid: 12730992
references.citation: J Neurosci. 2012 May 30;32(22):7499-518
references.pmid: 22649229
references.citation: J Neurosci. 2002 Apr 1;22(7):2451-9
references.pmid: 11923409
references.citation: Biochem Biophys Res Commun. 2013 Oct 18;440(2):336-41
references.pmid: 24076392
references.citation: Mol Cell Neurosci. 2004 Feb;25(2):301-11
references.pmid: 15019946
references.citation: Brain Pathol. 2010 Sep;20(5):909-25
references.pmid: 20406232
references.citation: Glia. 2015 May;63(5):768-79
references.pmid: 25557204
references.citation: J Immunol. 2000 Aug 15;165(4):2232-9
references.pmid: 10925311
references.citation: J Cereb Blood Flow Metab. 2007 Feb;27(2):334-47
references.pmid: 16757980
references.citation: Semin Neurol. 2012 Sep;32(4):374-400
references.pmid: 23361483
references.citation: J Neurosci Res. 2003 Apr 1;72(1):12-24
references.pmid: 12645075
references.citation: Nat Med. 1998 Mar;4(3):291-7
references.pmid: 9500601
references.citation: Neuron. 2011 May 26;70(4):661-73
references.pmid: 21609823
references.citation: Glia. 2005 Oct;52(1):36-46
references.pmid: 15892126
references.citation: Ann Neurol. 2012 Sep;72(3):395-405
references.pmid: 23034912
references.citation: Mol Cell Neurosci. 2002 Dec;21(4):602-15
references.pmid: 12504593
references.citation: Glia. 2006 Nov 15;54(7):666-75
references.pmid: 17006895
references.citation: Neuroimage. 2011 Apr 1;55(3):880-90
references.pmid: 21182970
references.citation: Nat Rev Neurol. 2010 Apr;6(4):193-201
references.pmid: 20234358
references.citation: Mol Cell Neurosci. 2002 Jul;20(3):489-502
references.pmid: 12139924
references.citation: J Anat. 2011 Jul;219(1):53-64
references.pmid: 21250988
references.citation: Prog Neurobiol. 2014 Jun;117:54-72
references.pmid: 24582777
references.citation: Glia. 2005 Nov 1;52(2):127-43
references.pmid: 15920731
references.citation: Neurobiol Dis. 2002 Mar;9(2):234-43
references.pmid: 11895374
references.citation: J Neurosci Res. 2002 Sep 15;69(6):966-75
references.pmid: 12205690
references.citation: Glia. 2012 Feb;60(2):281-94
references.pmid: 22042562
references.citation: Interdiscip Top Gerontol. 2014;39:86-107
references.pmid: 24862016
references.citation: Nature. 2012 May 24;485(7399):517-21
references.pmid: 22622581
references.citation: Mol Cell Neurosci. 2004 Feb;25(2):252-62
references.pmid: 15019942
references.citation: J Neuroimmunol. 1999 Jul 1;98(1):69-76
references.pmid: 10426364
references.citation: Prog Neurobiol. 2013 Jul-Aug;106-107:1-16
references.pmid: 23583307
references.citation: Neuroscience. 2010 Nov 24;171(1):235-44
references.pmid: 20833231
references.citation: Front Cell Neurosci. 2013 Oct 29;7:201
references.pmid: 24194700
references.citation: PLoS One. 2011;6(5):e20430
references.pmid: 21647369
references.citation: PLoS Med. 2008 Aug 19;5(8):e171
references.pmid: 18715114
references.citation: Annu Rev Neurosci. 2011;34:21-43
references.pmid: 21692657
references.citation: J Neurotrauma. 2010 Aug;27(8):1529-40
references.pmid: 20504161
references.citation: Neuroimage. 2010 Oct 1;52(4):1487-94
references.pmid: 20493952
references.citation: Glia. 2014 Nov;62(11):1780-9
references.pmid: 25043122
references.citation: J Neuropathol Exp Neurol. 1998 Mar;57(3):231-8
references.pmid: 9600215
references.citation: Transl Stroke Res. 2014 Feb;5(1):17-27
references.pmid: 24323733
references.citation: Phys Med Rehabil Clin N Am. 2011 Nov;22(4):683-700, ix
references.pmid: 22050943
references.citation: Biochem J. 2009 Jan 1;417(1):1-13
references.pmid: 19061483
references.citation: Neurology. 2009 May 19;72(20):1779-85
references.pmid: 19451534
references.citation: Glia. 2012 May;60(6):875-81
references.pmid: 22392631
references.citation: Semin Pediatr Neurol. 2013 Sep;20(3):194-201
references.pmid: 24331361
references.citation: Curr Opin Neurobiol. 2013 Dec;23(6):1065-72
references.pmid: 24094633
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: EMBO Mol Med. 2010 Feb;2(2):42-50
references.pmid: 20091761
references.citation: Nat Neurosci. 2007 Mar;10(3):311-20
references.pmid: 17293860
references.citation: Biochimie. 2014 Mar;98:111-8
references.pmid: 24120688
references.citation: Neuroscience. 2010 Jul 28;168(4):982-1008
references.pmid: 19850107
references.citation: Brain. 2013 Jan;136(Pt 1):116-31
references.pmid: 23365094