title: Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex.
abstract: Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination. Moreover, progesterone has been demonstrated to promote myelin formation in organotypic cultures of cerebellar slices. In the present study, we show that progesterone and the synthetic 19-nor-progesterone derivative Nestorone® promote the repair of severe chronic demyelinating lesions induced by feeding cuprizone to female mice for up to 12 weeks. Progesterone and Nestorone increase the density of NG2(+) oligodendrocyte progenitor cells and CA II(+) mature oligodendrocytes and enhance the formation of myelin basic protein (MBP)- and proteolipid protein (PLP)-immunoreactive myelin. However, while demyelination in response to cuprizone was less marked in corpus callosum than in cerebral cortex, remyelination appeared earlier in the former. The remyelinating effect of progesterone was progesterone receptor (PR)-dependent, as it was absent in PR-knockout mice. Progesterone and Nestorone also decreased (but did not suppress) neuroinflammatory responses, specifically astrocyte and microglial cell activation. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin.
authors.affiliation: UMR 788 Inserm and University Paris-Sud, 94276, Kremlin-Bicêtre, France.
authors.forename: Martine
authors.initials: M
authors.lastname: El-Etr
authors.forename: Marion
authors.initials: M
authors.lastname: Rame
authors.forename: Celine
authors.initials: C
authors.lastname: Boucher
authors.forename: Abdel M
authors.initials: AM
authors.lastname: Ghoumari
authors.forename: Narender
authors.initials: N
authors.lastname: Kumar
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.forename: Antoine
authors.initials: A
authors.lastname: Pianos
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.forename: Regine
authors.initials: R
authors.lastname: Sitruk-Ware
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003337:Corpus Callosum / Q000187:drug effects* / Q000473:pathology; D003471:Cuprizone / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D011374:Progesterone; D003471:Cuprizone
keywords: cuprizone; oligodendrocytes; progesterone receptor; progestogens; remyelination
references.citation: Acta Neuropathol. 2009 Dec;118(6):723-36
references.pmid: 19763593
references.citation: Neurosci Lett. 2010 May 26;476(1):42-5
references.pmid: 20381586
references.citation: J Neuropathol Exp Neurol. 2006 Mar;65(3):245-56
references.pmid: 16651886
references.citation: J Neurochem. 2003 Aug;86(4):848-59
references.pmid: 12887683
references.citation: Expert Opin Drug Discov. 2013 Feb;8(2):115-29
references.pmid: 23231597
references.citation: J Neurosci. 2008 Dec 24;28(52):14189-201
references.pmid: 19109501
references.citation: Neurosci Lett. 2009 Apr 3;453(2):120-5
references.pmid: 19356606
references.citation: Neurochem Res. 2010 Sep;35(9):1422-33
references.pmid: 20544279
references.citation: Lancet Neurol. 2012 Dec;11(12):1082-92
references.pmid: 23153407
references.citation: Prog Neurobiol. 2014 Feb;113:1-5
references.pmid: 24121112
references.citation: Neuropathol Appl Neurobiol. 2004 Feb;30(1):80-9
references.pmid: 14720179
references.citation: Cell. 2007 Oct 19;131(2):405-18
references.pmid: 17956739
references.citation: J Comp Neurol. 2008 Nov 1;511(1):34-46
references.pmid: 18720413
references.citation: Prog Brain Res. 2009;175:219-37
references.pmid: 19660659
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):19125-30
references.pmid: 24191028
references.citation: Brain. 2008 Feb;131(Pt 2):318-28
references.pmid: 17715141
references.citation: Steroids. 2000 Oct-Nov;65(10-11):629-36
references.pmid: 11108869
references.citation: Contraception. 2010 Nov;82(5):410-7
references.pmid: 20933114
references.citation: Endocrinology. 2010 Dec;151(12):5782-94
references.pmid: 20943809
references.citation: Nat Rev Neurol. 2010 Aug;6(8):438-44
references.pmid: 20625376
references.citation: Brain. 2007 Aug;130(Pt 8):2199-210
references.pmid: 17557778
references.citation: Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2
references.pmid: 17011666
references.citation: J Neurosci. 1982 Oct;2(10):1446-52
references.pmid: 6889633
references.citation: Glia. 2006 Jul;54(1):1-10
references.pmid: 16652341
references.citation: Glia. 2009 Jun;57(8):884-97
references.pmid: 19053058
references.citation: Endocrinology. 2011 Oct;152(10):3820-31
references.pmid: 21828184
references.citation: Mol Endocrinol. 2002 Nov;16(11):2475-89
references.pmid: 12403837
references.citation: Neuroscience. 2011 Sep 29;192:588-97
references.pmid: 21736923
references.citation: Trends Neurosci. 1992 Dec;15(12):501-8
references.pmid: 1282751
references.citation: Contraception. 2007 Dec;76(6):432-8
references.pmid: 18061700
references.citation: Nat Rev Neurosci. 2008 Jun;9(6):481-93
references.pmid: 18490917
references.citation: Brain Pathol. 2001 Jan;11(1):107-16
references.pmid: 11145196
references.citation: J Neuroimmunol. 2010 Mar 30;220(1-2):136-9
references.pmid: 20153059
references.citation: Am J Pathol. 2008 Apr;172(4):1053-61
references.pmid: 18349131
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8867-72
references.pmid: 21555578
references.citation: Immunology. 2009 Mar;126(3):329-35
references.pmid: 19302141
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):173-87
references.pmid: 19318112
references.citation: J Neurosci Res. 2011 Jan;89(1):13-21
references.pmid: 20857501
references.citation: Annu Rev Neurosci. 2008;31:535-61
references.pmid: 18558866
references.citation: Nat Rev Neurol. 2010 May;6(5):247-55
references.pmid: 20404843
references.citation: Exp Cell Res. 1991 Mar;193(1):12-9
references.pmid: 1995287
references.citation: Brain Res. 1989 Feb 20;480(1-2):1-15
references.pmid: 2713643
references.citation: Horm Behav. 1997 Jun;31(3):244-55
references.pmid: 9213138
references.citation: J Steroid Biochem Mol Biol. 2007 Nov-Dec;107(3-5):228-37
references.pmid: 17692515
references.citation: Prog Neurobiol. 2014 Feb;113:6-39
references.pmid: 24172649
references.citation: Nat Rev Neurol. 2012 Nov 5;8(11):624-34
references.pmid: 23026979
references.citation: Brain Res. 1989 Aug 21;495(1):75-82
references.pmid: 2776038
references.citation: Genes Dev. 1995 Sep 15;9(18):2266-78
references.pmid: 7557380
references.citation: Stem Cells. 2010 Sep;28(9):1611-22
references.pmid: 20672298
references.citation: Glia. 2009 Jun;57(8):807-14
references.pmid: 19031445
references.citation: Endocrinology. 2012 Aug;153(8):3747-57
references.pmid: 22635678
references.citation: J Neurosci. 2001 Aug 15;21(16):6221-32
references.pmid: 11487645
references.citation: Biochem Biophys Res Commun. 2002 Apr 26;293(1):106-11
references.pmid: 12054570
references.citation: Crit Care. 2008;12(2):R61
references.pmid: 18447940
references.citation: J Neurosci Res. 2010 Feb 1;88(2):391-402
references.pmid: 19746424
references.citation: Am J Pathol. 2004 May;164(5):1673-82
references.pmid: 15111314
references.citation: Science. 1995 Jun 9;268(5216):1500-3
references.pmid: 7770777
references.citation: Glia. 2008 Apr 15;56(6):659-74
references.pmid: 18286612
references.citation: Dialogues Clin Neurosci. 2011;13(3):352-9
references.pmid: 22033509
references.citation: Reproduction. 2007 May;133(5):1035-44
references.pmid: 17616732
references.citation: Neurobiol Dis. 2005 Feb;18(1):166-75
references.pmid: 15649707
references.citation: Brain. 2013 Jan;136(Pt 1):132-46
references.pmid: 23365095
references.citation: CNS Neurol Disord Drug Targets. 2012 Aug;11(5):570-88
references.pmid: 22583443
references.citation: Ann Neurol. 2002 Feb;51(2):215-23
references.pmid: 11835378
references.citation: Trends Pharmacol Sci. 2005 Jan;26(1):27-35
references.pmid: 15629202
references.citation: Brain. 2012 Oct;135(Pt 10):2952-61
references.pmid: 23065788
references.citation: J Neuroendocrinol. 2012 Jun;24(6):851-61
references.pmid: 22283602
references.citation: Nat Rev Neurol. 2014 Apr;10(4):225-38
references.pmid: 24638138
references.citation: Nat Rev Neurol. 2011 May;7(5):255-62
references.pmid: 21467994
references.citation: Am J Pathol. 2003 Oct;163(4):1599-605
references.pmid: 14507666