Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system.
We report here that curative treatment of the multiple sclerosis paradigm, chronic relapsing experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, by 1,25-dihydroxyvitamin D(3 )(1,25-D3) leads to a rapid clinical improvement accompanied by an inhibition of CD4, MHC class II and type II nitric oxide synthase (NOS II) expression in the posterior areas of the central nervous system (CNS). In contrast, the hormone has no effect on transforming growth factor-beta1 transcripts. Computer analysis of the NOS II promoter, expressed by microglia and astrocytes, reveals consensus sequence for vitamin D receptor binding, emphasizing the idea that 1,25-D3 may regulate some aspects of EAE by acting directly on CNS constituent cells. We also demonstrate that vitamin D deprivation leads to minimal effects on the kinetic profile of EAE accompanied by a moderate exacerbation of the clinical symptoms. Interestingly, curative treatment of vitamin D-deprived rats with a non-toxic-1,25-D3 analogue (MC1288) strongly inhibited EAE symptoms, thus promulgating the potential interest of such compounds in the management of multiple sclerosis.
Garcion
Emmanuel
E
INSERM ERIT-M 0104, 10 rue André Boquel, 49100 Angers, France. emmanuel.garcion@univ-angers.fr
Sindji
Laurence
L
Nataf
Serge
S
Brachet
Philippe
P
Darcy
Françoise
F
Montero-Menei
Claudia N
CN
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001931:Brain Mapping; D015704:CD4 Antigens / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology / Q000627:therapeutic use*; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D016022:Case-Control Studies; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D017421:Sequence Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D001426:Bacterial Proteins; D015704:CD4 Antigens; D002120:Calcium Channel Agonists; D016177:Macrophage-1 Antigen; C095564:Map protein, Staphylococcus aureus; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D002117:Calcitriol