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. 2013 Nov;183(5):1390-1396.
doi: 10.1016/j.ajpath.2013.07.006. Epub 2013 Oct 1.

Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis

Fumitaka Sato  1 , Nicholas E Martinez  1 , Maira Shahid  2 , John W Rose  3 , Noel G Carlson  4 , Ikuo Tsunoda  5
Affiliations

Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis

Fumitaka Sato et al. Am J Pathol. 2013 Nov.

Abstract

The polyphenol compound resveratrol is reported to have multiple functions, including neuroprotection, and no major adverse effects have been reported. Although the neuroprotective effects have been associated with sirtuin 1 activation by resveratrol, the mechanisms by which resveratrol exerts such functions are a matter of controversy. We examined whether resveratrol can be neuroprotective in two models of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). EAE was induced in C57BL/6 mice, which were fed a control diet or a diet containing resveratrol during either the induction or effector phase or through the whole course of EAE. SJL/J mice were infected with TMEV and fed a control diet or a diet containing resveratrol during the chronic phase of TMEV-IDD. In EAE, all groups of mice treated with resveratrol had more severe clinical signs than the control group. In particular, resveratrol treatment during the induction phase resulted in the most severe EAE, both clinically and histologically. Similarly, in the viral model, the mice treated with resveratrol developed significantly more severe TMEV-IDD than the control group. Thus, surprisingly, the resveratrol treatment significantly exacerbated demyelination and inflammation without neuroprotection in the central nervous system in both models. Our findings indicate that caution should be exercised in potential therapeutic applications of resveratrol in human inflammatory demyelinating diseases, including multiple sclerosis.

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Figures

Figure 1
Figure 1
Adverse effects of resveratrol in the EAE autoimmune model of MS. C57BL/6 mice were sensitized with MOG35-55 on day 0 and were fed either a control diet or a diet containing resveratrol on days −1 to 8 (Early) or days 14 to 23 (Late) or days −1 to 63 (Whole). A: All three resveratrol-treated groups develop more severe EAE, compared with the Control group, although all groups had a similar disease onset. B: Control EAE mice have inactive demyelinating lesions in the dorsal funiculus of the spinal cord. Mice treated with resveratrol during the induction phase of EAE have more severe demyelination (arrowheads), meningitis (arrows), and active perivascular inflammation (paired arrows), compared with control mice. Luxol fast blue staining. C: Mice fed a diet containing resveratrol during the induction phase of EAE have significantly higher spinal cord pathology scores in demyelination, meningitis, perivascular cuffing (indicative of inflammation), and overall pathology, compared with mice fed a control diet. Mice treated with resveratrol during the whole course of the experiment have significantly higher scores in meningitis and overall pathology, compared with control mice. D: Brain pathology score does not differ significantly among the groups. Data are expressed as means (A) or as means ± SEM (C and D). n = 5 or 6 symptomatic mice per group. ∗P < 0.05, ∗∗P < 0.01, ANOVA. Original magnification, ×41. Scale bar = 100 μm.
Figure 2
Figure 2
Axonal degeneration, 2 months after EAE induction. EAE mice were given a control diet or a diet containing resveratrol on days −1 to 8 (Early), days 14 to 23 (Late), or days −1 to 63 (Whole). A: Immunohistochemistry for nonphosphorylated neurofilament reveals higher levels of axonal damage (arrows) in the Early group than in the Control group. Boxed regions are shown at higher magnification in the corresponding inset. B: Higher numbers of nonphosphorylated neurofilament-positive damaged axons are detected in the spinal cord of mice fed a diet containing resveratrol during the induction phase of EAE, compared with control mice. Data are expressed as means ± SEM. n = 5 or 6 symptomatic mice per group. ∗∗P < 0.01, ANOVA. Original magnification: ×83; ×115 (insets). Scale bars: 50 μm (A).
Figure 3
Figure 3
Adverse effects of resveratrol in the TMEV viral model of MS. SJL/J mice were infected intracerebrally with 2 × 105 PFU of the DA strain of TMEV on day 0 and were fed a control diet (DA alone, black bars) or a diet containing resveratrol from day 35 to day 48 (Chronic, white bars). A: The TMEV-infected mice treated with a resveratrol diet develop more severe clinical signs than mice on the control diet. B: Mice treated with a resveratrol diet have more severe demyelination (arrowheads), meningitis (arrows), and active perivascular inflammation (paired arrows) than mice on the control diet. Luxol fast blue staining. C: The TMEV-infected mice fed resveratrol have significantly higher pathology scores in demyelination, meningitis, and perivascular cuffing (inflammation) than mice fed a control diet. D: There is a small but nonsignificant difference in brain pathology scores between the two groups. Data are expressed as means (A) or as means ± SEM (C and D). n = 8 mice per group. ∗P < 0.05, ∗∗P < 0.01, ANOVA. Original magnification, ×42. Scale bars: 100 μm (B).
Figure 4
Figure 4
Axonal degeneration, 2 months after TMEV infection. SJL/J mice were infected with the DA strain of TMEV and fed a control diet (DA alone, black bar) or a diet containing resveratrol from day 35 to day 48 (Chronic, white bar). A: Levels of damaged axons (arrows) in the spinal cord are similar in the two groups. Immunohistochemistry for nonphosphorylated neurofilament. B: Nonphosphorylated neurofilament-positive damaged axons in the spinal cord are similar in the two groups. Data are expressed as means ± SEM. n = 8 mice per group. Original magnification, ×83. Scale bars: 50 μm (A).
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