A Novel Combination of Docosahexaenoic Acid, All-Trans Retinoic Acid, and 1, 25-Dihydroxyvitamin D3 Reduces T-Bet Gene Expression, Serum Interferon Gamma, and Clinical Scores but Promotes PPARγ Gene Expression in Experimental Autoimmune Encephalomyelitis

Abstract

Vitamins are immunologically interesting due to their significant immunomodulatory activities. Experimental autoimmune encephalomyelitis (EAE) is one of the most commonly used experimental models for studying autoimmune disorder in multiple sclerosis (MS). The aim of this study was to evaluate the protective and ameliorative effects of novel combination of all-trans retinoic acid (ATRA), 1,25-dihydroxyvitamin D (D), and docosahexaenoic acid (DHA) on EAE-specific determinants and target gene expressions. Mice were randomly categorized into three groups before EAE induction [non-treated EAE (Group E), treated EAE (Group T), and healthy mice (Group H)]. Encephalomyelitis was induced in female C57BL/6 mice by subcutaneous immunization using commercial kits. Preceding day of EAE induction, combination of ATRA, D, and DHA was administered with a single IP injection every 48 h and continued until day 26. Findings of present study showed that administration of vitamins A, D, and DHA significantly decreased average clinical scores, cumulative EAE score, and EAE incidence in Group T, compared to Group E (p values <0.001). Interferon γ secretion in serum and T-bet mRNA expression in splenocytes were significantly reduced (p = 0.004, p = 0.029, respectively) while PPARγ mRNA expression was significantly increased in Group T compared to Group E (p = 0.021). These findings highlighted that ATRA, D, and DHA combination modulated PPARγ and T-bet gene expression and resulted in decrease in Th1 response and lymphocyte invasion into the central nervous system (CNS) and resultant inflammation. In conclusion, the results of this study suggested the potential use of this intervention in treatment and/or prevention of EAE/MS and probably other Th1 cell-mediated autoimmune diseases.

Nutrition in Multiple Sclerosis: An integrative review of scientific publications from the last 5 years

“…There was also a predominance of studies (19.0%; n= 12) that assessed the role of antioxidant vitamins (A, C and/or E) in the development and/or evolution of MS [9][10][11][12][13][14][15][16][17][18][19][20] and the influence of some natural bioactive compounds, flavonoids and non-flavonoids with antioxidant and/or anti-inflammatory power (12.7%, n= 8), in the disease development, in particular in demyelination 21 control, and consequently, in the progress of symptoms such as muscular weakness and fatigue 22 .…”

“…There were a total of 101 dietary components/nutritional patterns studied because some studies assessed more than one of these components. 56 ; Jelinek et al 52 ; Koriem 57 ; Malli et al 31 ; Masullo et al 13 ; Peterlik 58 ; Polachini et al 16 ; Romero et al 59 ; Schmitz et al 18 ; Shiri-Shahsavar et al 19 ; Torkildsen et al 20 63 ; Hoare et al 62 ; Mauriz et al 14 ; Nieto et al 15 ; Pantzaris et al 61 ; Rezapour-Firouzi et al 28 ; Rezapour-Firouzi et al 30 ; Schmitz et al 18 ; Shiri-Shahsavar et al 19 ; Timmermans et al 60 ; Weiland et al 43 Antioxidant Vitamins 12 19.0 Dorosty-Motlagh et al 9 ; Geldern; Mowry 10 ; Honarvar et al 11 ; Loken-Amsrud 12 ; Masullo et al 13 ; Mauriz et al 14 ; Nieto et al 15 ; Polachini et al 16 ; Saboor-Yaraghi et al 17 ; Schmitz et al 18 ; Shiri-Shahsavar et al 19 ; Torkildsen et al 20 Bioactive compounds 8 12. Hagan et al 35 ; Jelinek et al 36 ; Oliveira et al 37 ; Wens et al 38 .…”

“…We noticed that the use of vitamin D supplements is common among people who suffer from this condition 3,52 , with a significant number of individuals claiming to have received a doctor recommendation in this sense 13 . We also note that there is much evidence that use of vitamin D supplements reduces MS risks and improves clinical results of those who have been diagnosed with the disease or with Clinically Isolated Syndrome 10,[16][17][18][19][20][21]31,35,39,43,[53][54][55][56][57][58][59] . However, it is also common for researchers to suggest that more observational studies and mainly, more randomized clinical trials, should be performed seeking to provide definitive evidence on whom, how, when and how much supplements should be administered for primary and secondary prevention and treatment 10,20,43,58 .…”

“…With regards to oils and fats, studies in animals or in vitro tests have predominantly evidenced that hypolipidemic 14,24,60 diets or those diets that replace saturated by polyunsaturated fat 18,21,61 , in particular ω-3 15,19,43,62 , may exert a neuroprotective effect. Among the several suggested mechanisms, we should mention the strengthening of the blood-brain barrier, which avoids immune cell and neurotoxin access to the CNS and the reduction of pro-inflammatory cytokine synthesis.…”

“…Vitamin A and its predecessors proved to be essential for immune system integrity. In the form of trans-retinoic acid or retinyl palmitate, the nutrient regulates the transition of unexpressive disease genes 12,18,19 such as the FoxP 9,17 , which helps in the proliferation of regulatory-T cells (Treg) and attenuates T helper 1 type ones. Tregs produce the secretion of TGF-β, which suppress the production of pro inflammatory cytokines (such as the IFN-γ) 9,11 .…”