Oral Resveratrol Reduces Neuronal Damage in a Model of Multiple Sclerosis

Abstract

Background Neuronal loss in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), correlates with permanent neurological dysfunction. Current MS therapies have limited ability to prevent neuronal damage. Methods We examined whether oral therapy with SRT501, a pharmaceutical-grade formulation of resveratrol, reduces neuronal loss during relapsing/remitting EAE. Resveratrol activates SIRT1, an NAD+-dependent deacetylase that promotes mitochondrial function. Results Oral SRT501 prevented neuronal loss during optic neuritis, an inflammatory optic nerve lesion in MS and EAE. SRT501 also suppressed neurological dysfunction during EAE remission, and spinal cords from SRT501-treated mice had significantly higher axonal density than vehicle-treated mice. Similar neuroprotection was mediated by SRT1720, another SIRT1-activating compound; and sirtinol, a SIRT1 inhibitor, attenuated SRT501 neuroprotective effects. SIRT1 activators did not prevent inflammation. Conclusions These studies demonstrate SRT501 attenuates neuronal damage and neurological dysfunction in EAE by a mechanism involving SIRT1 activation. SIRT1 activators are a potential oral therapy in MS.

Use of engineered bone marrow stem cells to deliver brain derived neurotrophic factor under the control of a tetracycline sensitive response element in experimental allergic encephalomyelitis

“…We also studied SIRT1 (Haigis and Guarente, 2006;Shindler et al, 2010;Rahman and Islam, 2011), a NAD-dependent protein deacetylase, because it has emerged as a regulator of mammalian transcription in the response to cellular metabolic stress with neuroprotective effects (Gao et al, 2010). We found that SIRT1 expressing cells increased in the spinal cord in transplanted mice with EAE compared to untransplanted normal mouse tissue and that the doxycycline treated transplanted mice with EAE had higher numbers of SIRT1 expressing cells than transplanted EAE mice that did not receive doxycycline.…”

Over-the-counter anti-oxidant therapies for use in multiple sclerosis: A systematic review

“…With the ongoing degeneration that is associated with progressive MS and the presence of OS at sites of degeneration, 2,8,9,79,80 determining the utility of anti-oxidant therapies to protect neural tissue or promote repair is a major research gap. In this review, we found that only EGCG, 37,38 vitamin E, 44,53 reservatrol, 33,35 and ALA 66,69,70 promoted remyelination and/ or protected neurons from inflammatory-mediated damage (in animal models). Resveratrol consistently provided neuroprotection in EAE, though this was independent of any anti-inflammatory benefits.…”

“…43 It is known to have poor bioavailability, so most studies administer SRT501, a pharmaceutical formulation of resveratrol that has enhanced systemic absorption. 33,43 In four studies reviewed (all in animal models), both resveratrol and SRT501 consistently decreased EAE severity, [33][34][35][36] which coincided with reduced optic nerve damage and prevention of retinal ganglion cell loss. 33,35 Resveratrol did not alter the levels of infiltrating immune cells into the spinal cord of EAE animals, suggesting it functions through a neuroprotective mechanism; [33][34][35] though one group reported decreased levels of peripheral pro-inflammatory cytokines.…”

“…Resveratrol consistently provided neuroprotection in EAE, though this was independent of any anti-inflammatory benefits. 33,35 Clinical studies included in this review provided short term outcomes (predominantly 12 weeks posttreatment) with no effects of OTC anti-oxidants on the disease course (EDSS score). If it is purported that anti-oxidants convey their benefits by interfering with the inflammatory cascade and preventing axonal damage then longer term outcomes, such as lesion accumulation, number of relapses, or recovery postrelapse, should be included in future studies.…”

“…24 They are believed to function through their anti-oxidant and radical scavenging activities. 25 Our review included 15 studies examining five compounds classified as polyphenols, where some studies examine more than one compound: quercetin, [26][27][28][29] luteolin, 26,29,30 curcumin, 29,31,32 resveratrol, [33][34][35][36] and epigallocatechin-3-gallate (EGCG). [37][38][39][40] Details of the included studies are found in Supplementary Table 3 and assessment of risk-of-bias in Supplementary Figure 2(a) and (b).…”