This work was supported by grants from the Swedish Research
Council (MJ (K2008-66X-20776-01-4 and K2012-99X-20776-05-3)),
OH (2011-3457) and GCB (K2011-80P-21816-01-4 and K2011-80X-
21817-01-4)), Harald and Greta Jeanssons Foundation (MJ), Swedish
Association for Persons with Neurological Disabilities (MJ), ÅkeWibergs
Foundation (MJ), Åke Löwnertz Foundation (MJ), Swedish Brain Foundation
(MJ and GCB), David and Astrid Hagélen Foundation (GCB),
Swedish Society for Medical Research (GCB), Swedish Society of Medicine
(GCB), Socialstyrelsen (MJ), Karolinska Institutet funds (MJ and
GCB), Marie Curie Integration Grant, Seventh Framework Programme,
European Union (GCB, PCIG12-GA-2012-333713)), Neuropromise
LSHM-CT-2005-018637 (MZA, HL) and Theme Center for Regenerative
Medicine at Karolinska Institutet (OH)

Alan Gillett

Ana Mendanha Falcão

André Ortlieb Guerreiro-Cacais

Baron

Brogdon

Camelo

Campas-Moya

Castelo-Branco

Chiu

Codarri

Colello

Dagtas

De Vito

de Zoeten

Deshmukh

Edens

Fancy

Fernandez

Gerstner

Glauben

Gonçalo Castelo-Branco

Goverman

Hans Lassmann

Hirota

Iglesias

IMSGC

Kang

Kedir Hussen Hamza

Kramer

Kroenke

Langrish

Leoni

Lucas

Maja Jagodic

Mann

Milena Z. Adzemovic

Mishra

Monica Marta

Moreira

Nait-Oumesmar

Nakahara

Nishida

Ola Hermanson

Olsson

Park

Perissi

Pernilla Stridh

Rafalski

Rasmus Berglund

Reboldi

Saouaf

Sebastian

Segal

Shen

Song

Steinman

Stolt

Storch

Stromnes

Tepavcevic

Villagra

Vinken

von Budingen

Wang

Zawadzka

Zhang

Neurobiology of Disease

AbstractMultiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4+ T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4+ T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and l-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4+ T cells and affected the Th1 differentiation program in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression

Castelo-Branco, Gonçalo

Stridh, Pernilla

Guerreiro-Cacais, André Ortlieb

Adzemovic, Milena Z.

Falcão, Ana Mendanha

Marta, Monica

Berglund, Rasmus

Gillett, Alan

Hamza, Kedir Hussen

Lassmann, Hans

Hermanson, Ola

Jagodic, Maja

Elsevier - Publisher Connector 

Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats 

Castelo-Branco, G

Stridh, P

Guerreiro-Cacais, AO

Adzemovic, MZ

Falcao, AM

Marta, M

Berglund, R

Gillett, A

Hamza, KH

Lassmann, H

Hermanson, O

Jagodic, M

Queen Mary Research Online

Acute treatment with valproic acid and l-thyroxine ameliorates clinicalsigns of experimental autoimmune encephalomyelitis and prevents brainpathology in DA rats.Castelo-Branco, G; Stridh, P; Guerreiro-Cacais, AO; Adzemovic, MZ; Falcão, AM; Marta, M;Berglund, R; Gillett, A; Hamza, KH; Lassmann, H; Hermanson, O; Jagodic, M     © 2014 The Authors. Published by Elsevier IncCC BY license  For additional information about this publication click this link.http://qmro.qmul.ac.uk/xmlui/handle/123456789/14910   Information about this research object was correct at the time of download; we occasionallymake corrections to records, please therefore check the published record when citing. Formore information contact scholarlycommunications@qmul.ac.uk37 20555 10342 17467 93IL-17IFN-γ62 3555 36Foxp3Ki670102030405060700510152025024680510152025Ki67+IL-17+IFN-g-IL-17+IFN-g+IL-17+**** ******* ***** ******T3VEHICLE VPA VPA/T3VEHICLE T3 VPA VPA/T3UNTREATEDα-H3K9acα-GAPDHABC00.51.01.52.02.53.02 4 6 8 10VEHICLET3VPAVPA/T30123450246810EAE scoreEAE durationCumulative score***************T3VEHICLE VPA VPA/T300.51.01.52.02.53.03.500.51.01.52.02.53.03.500.51.01.52.02.53.03.5EAE scoreEAE scoreEAE score***321032103210******EAE scoreEAE scoreEAE score*******EBA00.51.01.52.02.53.03.5EAE score***3210EAE score ***C0 5 10 15 20 25 30 35Days post immunization (p.i.)10 20 30Days p.i.VPA/T4VEHICLEVPA/T4VEHICLEDEAEinductionFirstsymptomsEach day:VPA i.p. 3x T4 s.c. 1xEach day:VPA i.p. 3x T4 s.c. 1x2  4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36DaysC0.000.050.100.150.200.00.51.01.52.02.5012345012345010203040012345601020300.000.020.040.060.080.100.00.20.40.60.81.00.00.40.81.21.6*0.000.020.040.060.08Sox8 expression0.000.010.020.030.040.05Sox8 expressionCNPase expressionCNPase expressionMbp expressionMbp expressionPlp expressionPlp expressionMag expressionMag expressionMog expressionMog expression* * ** ** **spinal cordbrainVPA/T4VEHICLEA BCD45CD11b O4Ki67A BCGated on ADEGated on DCD45O4 05101520% of O4+ Ki67+0102030012051015brainspinal cord% of O4+ Ki67+% of total% of totalO4+Ki67+ O4+Ki67+CD4+ Foxp3-02004006008000500100015002000*020406080100020406080 p=0.06IFN-g+IL-17-050100150200050100150200 *010020030040005010015020002040608010002040608010005101520 p=0.0601020304050 **Cell numberCell numberCell numberCell number% of total% of CD4+ Foxp3-Cell numberCell numberCell numberCell numberVPA/T4VEHICLEVPA/T4VEHICLEABspinal cordbrainIL-17IFN-γCD4CD4SSC Foxp3% of total% of CD4+ Foxp3-% of CD4+ Foxp3-% of CD4+ Foxp3-% of CD4+ Foxp3-% of CD4+ Foxp3-IFN-g+IL-17+ IFN-g-IL-17+010203040010203040500246810051015A BGated on A Gated on B*p=0.1 **CD3+CD8-CD3+CD8+CD3+CD8-Foxp3+CD3+CD8+Foxp3+***CD4+Foxp3+Ki67+CD4+Foxp3-Ki67+CD8+Foxp3+Ki67+CD8+Foxp3-Ki67+ABVPA/T4VEHICLE** **IFN-g+IL-17-IFN-g+IL-17+IFN-g-IL-17+02040608010005101520253005101520253002468051015202530010203040500102030400102030405001020304050012301234CD4+ T cells CD8+ T cellsCD8CD310.8 7.721.5 59.813.5 10.210.165.96.3 1.417.974.34.5 1.224.969.1Ki67Foxp382.0 14.528.768.1CD3CD45RA9.39.1VEHICLEVPA/T4Gated on AAAB CB CGated on B Gated on C00.51.01.52.02.53.03.5VPA/T4VEHICLE020406080100020406080100demyelinationno demyelination**Demyelination scoreDemyelination scoreAnimals (%)Animals (%)ABVPA/T4VEHICLEspinal cordbrainVPA/T4VEHICLE00.51.01.52.02.53.03.5A1 A2A3 A4B1 B2B3 B4

Acute treatment with valproic acid and L-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats

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Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/14910/Figures_CasteloBranco_NBD.pdf?sequence=2

Acute treatment with valproic acid and L-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats

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