Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis.
OBJECTIVE
Based on evidence that pregnant women with multiple sclerosis (MS) show a decline in the relapse rate during the third trimester and an increase during the first 3 months postpartum, the suggestion was made that high levels of circulating sex steroids are responsible for pregnancy-mediated neuroprotection. As both estradiol (E(2)) and progesterone exert neuroprotective and myelinating effects on the nervous system, the effects of sex steroids were studied in the experimental autoimmune encephalomyelitis (EAE) model of MS.


METHODS
EAE was induced in female C57BL/6 mice by administration of a myelin oligodendrocyte protein (MOG(40-45)) peptide. Clinical signs of EAE, myelin protein expression and neuronal parameters were determined in mice with or without hormonal treatment.


RESULTS
Progesterone given prior to EAE induction attenuated the clinical scores of the disease, slightly delayed disease onset and decreased demyelination foci, according to luxol fast blue staining (LFB), myelin basic protein (MBP) and proteolipid protein (PLP) and mRNA expression. Motoneuron expression of Na,K-ATPase mRNA was also enhanced by progesterone. In turn, combined E(2) plus progesterone therapy more effectively prevented neurological deficits, fully restored LFB staining, MBP and PLP immunoreactivity and avoided inflammatory cell infiltration. On the neuronal side, steroid biotherapy increased brain-derived neurotrophic factor (BDNF) mRNA.


CONCLUSIONS
Early treatment with progesterone alone or more evidently in combination with E(2) showed a clinical benefit and produced myelinating and neuroprotective effects in mice with MOG(40-45)-induced EAE. Therefore, sex steroids should be considered as potential novel therapeutic strategies for MS.
Garay
Laura
L
Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
Gonzalez Deniselle
Maria Claudia
MC
Gierman
Lobke
L
Meyer
Maria
M
Lima
Analia
A
Roig
Paulina
P
De Nicola
Alejandro F
AF
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009490:Neurosecretory Systems / Q000276:immunology*; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol; D000254:Sodium-Potassium-Exchanging ATPase