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

Castelo‐Branco, Gonçalo; Stridh, Pernilla; Guerreiro-Cacais, André Ortlieb; Adzemovic, Milena Z.; Falcão, Ana Mendanha; Marta, Mónica; Berglund, Rasmus; Gillett, Alan; Hamza, Kedir Hussen; Lassmann, Hans; Hermanson, Ola; Jagodic, Maja

doi:10.1016/j.nbd.2014.08.019

Cited by 37 publications

(23 citation statements)

References 59 publications

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“…TH supplementation also restores oligodendroglial lineage and OL maturation from neural stem/progenitor cells (NSCs) derived from inflamed animal brains (Fernández et al, ). These results have been confirmed by other labs in the cuprizone demyelination model in mouse (Harsan et al, ) and rat (Castelo‐Branco et al, ; Franco et al, ; Silvestroff et al, ). Contrasting results have been obtained by TH treatment in perinatal inflammation‐induced white matter injury, either positive (perinatal hypoxa‐ischemia, Hung et al, ; intraventricular hemorrhage, Vose et al, ), or no effects (white matter injury induced by interleukin‐1β, Schang et al, ).…”

Section: Introductionsupporting

confidence: 76%

Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure

Fernández

Baldassarro

Sivilia

et al. 2016

Glia

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Differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is severely impaired by inflammatory cytokines and this could lead to remyelination failure in inflammatory/demyelinating diseases. Due to the role of thyroid hormone in the maturation of OPCs and developmental myelination, in this study we investigated (i) the possible occurrence of dysregulation of thyroid hormone signaling in the CNS tissue during experimental neuroinflammation; (ii) the possible impact of inflammatory cytokines on thyroid hormone signaling and OPCs differentiation in vitro. The disease model is the experimental allergic encephalomyelitis in female Dark-Agouti rats, whereas in vitro experiments were carried out in OPCs derived from neural stem cells. The main results are the following: (i) a strong upregulation of cytokine mRNA expression level was found in the spinal cord during experimental allergic encephalomyelitis; (ii) thyroid hormone signaling in the spinal cord (thyroid hormone receptors; deiodinase; thyroid hormone membrane transporter) is substantially downregulated, due to the upregulation of the thyroid hormone inactivating enzyme deiodinase 3 and the downregulation of thyroid hormone receptors, as investigated at mRNA expression level; (iii) when exposed to inflammatory cytokines, deiodinase 3 is upregulated in OPCs as well, and OPCs differentiation is blocked; (iv) deiodinase 3 inhibition by iopanoic acid recovers OPCs differentiation in the presence on inflammatory cytokines. These data suggest that cellular hypothyroidism occurs during experimental allergic encephalomyelitis, possibly impacting on thyroid hormone-dependent cellular processes, including maturation of OPCs into myelinating oligodendrocytes. GLIA 2016;64:1573-1589.

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Section: Introductionsupporting

confidence: 76%

Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure

Fernández

Baldassarro

Sivilia

et al. 2016

Glia

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“…The anti-inflammatory effect of HDAC inhibitors is not a new discovery; this phenomenon had previously been observed in other studies using different models of inflammatory disease [ 6 , 19 , 20 ]. However, the results presented in this paper describe this effect for the first time using an in vitro infection model with DENV, opening an approach for the development of pharmacological treatments using HDAC inhibitors against DENV-induced disease.…”

Section: Discussionmentioning

confidence: 72%

Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus

2018

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Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease-specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs) regulates the immune response in several inflammatory disease models. The aim of the current study was to evaluate the effect of HDAC inhibition in the production of inflammatory cytokines in human monocyte-derived macrophages infected with DENV serotype 2 (DENV-2). To this end, human monocyte-derived macrophages (MDMs) were treated with valproic acid (VPA) before or after infection and the inflammatory cytokine concentration was quantified by flow cytometry. We found that infected MDMs secreted IL-8, IL-1b, IL-6, TNF-alpha, and IL-10, but not IL-12. Strikingly, treatment of infected cells with VPA had a differential and concentration-dependent effect on the production of specific cytokines without eliciting significant changes in cell viability. Using the highest concentration of VPA, a significant reduction in the production of all cytokines was observed. These results suggest that HDAC inhibition during DENV-2 infection could exert an important regulatory effect in the production of inflammatory cytokines, representing a significant advance in the design of novel therapeutic dengue treatments.

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“…These changes may explain the observed significant reduction in frequency of highly pathogenic Th17 cells, observed both in actively induced MOG-EAE and in MBP 63-88 -specific T cells treated in vitro, because it has been shown that DNA methylation controls the high plasticity of Th17 cells (45). Interestingly, the transcription profile induced by vitamin D supplementation resembled that induced by valproic acid, which is a class I and II histone deacetylase (HDAC) inhibitor that also causes genome-wide DNA demethylation (46) and proteosomal degradation of HDAC2 (47) and has been shown by us and others to ameliorate EAE and affect Th17 cells (48,49). This finding suggests that vitamin D might share protective mechanisms with other epigenetic drugs.…”

Section: Discussionmentioning

confidence: 94%

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Zeitelhofer

Adzemovic

Gomez-Cabrero

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS. Vitamin D deficiency is one of the most consistently reported environmental factor in the etiology of multiple sclerosis (MS) (5), a chronic inflammatory disease of the CNS characterized by autoimmune destruction of myelin, axonal loss, and brain atrophy (6). Increased risk of developing MS has been described in carriers of rare and common variants of the CYP27B gene (7, 8), which encodes the enzyme that catalyzes the last step in converting vitamin D to its active form, from 25(OH)D 3 to 1,25 (OH) 2 D 3 . These studies imply a causal role of low vitamin D in MS, which has recently been further supported by Mendelian randomization studies in two large cohorts demonstrating that three genetic variants that associate with serum 25(OH)D 3 levels also associate with the risk of developing MS (9). However, high levels of vitamin D have been associated not only with the reduced risk of developing MS (10, 11) but also with the reduced risk for relapses, new brain lesions, and subsequent disability (12, 13). Moreover, it has been described that increased levels of vitamin D can reduce serum levels of . Most of what is known about the immunological mechanisms of vitamin D in MS comes from the studies in its animal model, experimental autoimmune encephalomyelitis (...

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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

Cited by 37 publications

References 59 publications

Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure

Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure

Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

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