title: Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.
abstract: OBJECTIVE
  Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice.
  
  
  METHODS
  A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method.
  
  
  RESULTS
  The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses.
  
  
  CONCLUSIONS
  The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model of CNS demyelination. These data support that apoE-mimetic strategy may represent a promising therapy for MS and other demyelination disorders.
authors: Department of Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, China ; Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Zhen
authors: Z
authors: Gu
authors: Cognosci, Inc. Research Triangle Park, NC 27709, USA ; Department of Neurology, Duke University Medical Center, Durham, 27708, NC, USA.
authors: Fengqiao
authors: F
authors: Li
authors: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA.
authors: Yi Ping
authors: YP
authors: Zhang
authors: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA.
authors: Lisa B E
authors: LB
authors: Shields
authors: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Xiaoling
authors: X
authors: Hu
authors: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Yiyan
authors: Y
authors: Zheng
authors: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Panpan
authors: P
authors: Yu
authors: Department of Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors: Yongjie
authors: Y
authors: Zhang
authors: Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Jun
authors: J
authors: Cai
authors: Cognosci, Inc. Research Triangle Park, NC 27709, USA ; Department of Neurology, Duke University Medical Center, Durham, 27708, NC, USA.
authors: Michael P
authors: MP
authors: Vitek
authors: Norton Neuroscience Institute, Norton Healthcare, Louisville, KY 40202, USA.
authors: Christopher B
authors: CB
authors: Shields
keywords: Apolipoprotein E-mimetic; COG112; Focal demyelination; Inflammation; Lysolecithin; Oligodendrocyte; Remyelination
references: J Pharmacol Exp Ther. 2011 Nov;339(2):519-29
references: 21807883
references: Neurology. 2001 Feb 13;56(3):312-6
references: 11171894
references: J Neuroinflammation. 2011 Nov 13;8:158
references: 22078261
references: Neuroreport. 2004 Apr 9;15(5):837-9
references: 15073526
references: J Neurosci. 2006 Jan 4;26(1):328-32
references: 16399703
references: Proc Natl Acad Sci U S A. 1983 Jul;80(13):4169-73
references: 6575401
references: Proc Natl Acad Sci U S A. 1986 Feb;83(4):1125-9
references: 2419900
references: J Neuroimmunol. 2004 Feb;147(1-2):62-7
references: 14741429
references: Pharmacol Biochem Behav. 2013 Feb;103(4):860-8
references: 23201649
references: J Neurotrauma. 2009 Jan;26(1):1-15
references: 19196178
references: Nature. 1974 Jun 7;249(457):577-8
references: 4834082
references: J Pharmacol Exp Ther. 2006 Sep;318(3):956-65
references: 16740622
references: J Biol Chem. 2003 Dec 5;278(49):48529-33
references: 14507923
references: Dev Neurobiol. 2013 Sep;73(9):713-22
references: 23696057
references: Prog Neurobiol. 1996 Dec;50(5-6):493-503
references: 9015824
references: Ann Neurol. 2004 Apr;55(4):458-68
references: 15048884
references: Neurology. 2001 Sep 11;57(5):853-7
references: 11552016
references: Glia. 2012 Oct;60(10):1468-80
references: 22689449
references: J Neurosci. 2010 Feb 24;30(8):2989-3001
references: 20181596
references: Mult Scler. 2003 Oct;9(5):476-80
references: 14582773
references: Adv Protein Chem. 1994;45:249-302
references: 8154371
references: Neuroimage. 2011 Jan 15;54(2):1565-77
references: 20804847
references: Nat Neurosci. 2012 Jun;15(6):862-70
references: 22610068
references: Neuropsychopharmacology. 2009 Jan;34(1):55-73
references: 18800062
references: Neurobiol Dis. 2013 Aug;56:59-65
references: 23619428
references: Nat Neurosci. 2010 May;13(5):541-50
references: 20418875
references: Nat Med. 2007 Oct;13(10 ):1228-33
references: 17906634
references: Exp Neurol. 2009 Nov;220(1):44-56
references: 19616545
references: Annu Rev Genomics Hum Genet. 2000;1:507-37
references: 11701639
references: Int J Oncol. 2009 Oct;35(4):665-72
references: 19724901
references: J Clin Invest. 1989 Mar;83(3):1015-31
references: 2493483
references: Science. 1985 Apr 26;228(4698):499-501
references: 3983637
references: Curr Top Microbiol Immunol. 2008;318:193-212
references: 18219819
references: Biochemistry. 2004 Jun 15;43(23):7328-35
references: 15182176
references: Neurodegener Dis. 2013;12(1):51-8
references: 22965147
references: Neuroscience. 2011 Sep 29;192:588-97
references: 21736923
references: J Pharmacol Exp Ther. 2010 Jul;334(1):106-15
references: 20406857
references: Neuron. 2009 Aug 13;63(3):287-303
references: 19679070
references: Science. 1988 Apr 29;240(4852):622-30
references: 3283935
references: Neurobiol Aging. 2002 Sep-Oct;23(5):777-85
references: 12392781
references: Lancet Neurol. 2011 Mar;10(3):241-52
references: 21349439
references: Ann Neurol. 2012 Sep;72(3):419-32
references: 23034914
references: Dev Dyn. 2007 Sep;236(9):2708-12
references: 17685481
references: J Lipid Res. 2001 Jul;42(7):1143-51
references: 11441143
references: Arch Gen Psychiatry. 2006 Jan;63(1):63-72
references: 16389198
references: Glia. 2002 Mar 1;37(3):241-9
references: 11857682
references: Neuroimage. 2009 May 1;45(4):1173-82
references: 19349232
references: J Neurosci. 2002 Jan 1;22(1):315-23
references: 11756515
references: J Mol Neurosci. 2012 Sep;48(1):77-85
references: 22552714
references: Acta Neurol Scand Suppl. 2012;(195):70-5
references: 23278660
references: J Neurotrauma. 2008 Oct;25(10):1227-40
references: 18986224
references: Exp Neurol. 2001 Jan;167(1):74-85
references: 11161595
references: Neurobiol Aging. 2009 Sep;30(9):1350-60
references: 18155324
references: J Neurosci Methods. 2007 Sep 15;165(1):9-17
references: 17628688
references: Mult Scler. 2002 Apr;8(2):98-103
references: 11990879
references: J Neurocytol. 1995 Oct;24(10):775-81
references: 8586997
references: J Biol Chem. 1990 Oct 15;265(29):17805-15
references: 2120218
references: Neuroscience. 2009 Nov 10;163(4):985-90
references: 19635528
references: Exp Neurol. 1999 Mar;156(1):191-204
references: 10192790
references: Nat Neurosci. 2005 Apr;8(4):468-75
references: 15793579
references: Free Radic Biol Med. 2002 Jun 1;32(11):1071-5
references: 12031891
references: J Neuroimmunol. 2003 Jan;134(1-2):44-51
references: 12507771