Resveratrol
Resveratrol (trans-3,5,4′-trihydroxystilbene) is a polyphenolic phytoestrogen found in some edible plants, including red grape skins, berries, and nuts. It has been attributed antioxidant and anti-inflammatory properties in scientific studies using animal models of MS.
In a model with optic neuritis, a common MS complication associated with vision loss and arising from nerve fiber damage and loss of nerve cells, high-absorption resveratrol was injected directly into the eye at a dose of 100 microM. Treatment was associated with significantly reduced loss of retinal ganglion cells (a type of neuron located near the inner surface of the retina of the eye) and preserved local nerve cell function long after the injection, compared to both pre-treatment and controls. However, there was no change in overall neurological condition of the animals1. In another study by the same research group, animals were administered either 500 mg/kg or 1000 mg/kg resveratrol orally, with significant reductions in nerve cell damage in both the eye and spinal cord, as well as neurological dysfunction. There was no apparent effect on myelination, inflammation, or immunologic function2.
Lower oral doses of 100 and 250 mg/kg resveratrol in EAE animals were observed to decrease clinical symptoms reflecting weakness and paralysis compared to pre-treatment and to a greater extent than in controls. Treatment also improved inflammatory responses, including greater inhibition of inflammatory3,4 and breakdown of inflammatory cells in the spinal cord4. These doses were also associated with delayed onset of disease and reduction in loss of neurons and retinal ganglion cells.5, as well as decreased immune cell infiltration and activation in the brain3.
Even lower doses of 25 and 50 mg/kg resveratrol were found to be protective of blood-brain barrier integrity, preventing infiltration of inflammatory and autoimmune factors6.
Of note, a single study using models of MS inflammation and demyelination found that resveratrol at a dose of 20 mg/kg worsened both disease processes, with no signs of neuroprotection7. While these results are alarming and give cause for caution, it may be more realistic to view them in the context of many other studies showing the opposite effect.
An extensive review of animal studies indicated that dietary resveratrol supplementation during pregnancy improved the status of the placenta status, which in turn is beneficial for the offspring’s well-being8.
In an animal model of gestational diabetes, resveratrol 147.6 mg/kg/day given orally to pregnant and lactating rats was shown to protect against glucose intolerance and pancreatic dysfunction in their offspring9, The dose was consistent with that in a previous animal study that found maternal resveratrol supplementation to be safe and not cause birth defects when taken during pregnancy, and at the same time to improve blood sugar metabolism10.
On a cautionary note, a very high dose of well over 1000 mg/day in pregnant monkeys was associated with impaired development of the pancreas in the fetus, even while it improved liver function11.
An extensive review of human studies using resveratrol in pregnancy concluded that it has numerous benefits on metabolic health for pregnant women and their offspring, indicating a therapeutic approach in pregnancy-related pathological conditions such as elevated inflammation, preeclampsia, and gestational diabetes. Therefore, although some adverse effects have been highlighted at a very high dose (1000 mg/day), clinical trials have suggested resveratrol to be safe, making its recommendation by physicians to pregnant women conceivable8.
Resveratrol is found naturally in grape skins, wine, grape juice, peanuts, cocoa, and berries of the Vaccinium species, including blueberries, bilberries, and cranberries12-16.
Refernces
1.Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A. SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci. Aug 2007;48(8):3602-9. doi:10.1167/iovs.07-0131
2.Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol. Dec 2010;30(4):328-39. doi:10.1097/WNO.0b013e3181f7f833
3.Gandy KAO, Zhang J, Nagarkatti P, Nagarkatti M. Resveratrol (3, 5, 4′-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain. J Neuroimmune Pharmacol. Sep 2019;14(3):462-477. doi:10.1007/s11481-019-09842-5
4.Singh NP, Hegde VL, Hofseth LJ, Nagarkatti M, Nagarkatti P. Resveratrol (trans-3,5,4′-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol. Dec 2007;72(6):1508-21. doi:10.1124/mol.107.038984
5.Fonseca-Kelly Z, Nassrallah M, Uribe J, et al. Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol. 2012;3:84. doi:10.3389/fneur.2012.00084
6.Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L. Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol. Nov 1 2016;116(5):2173-2179. doi:10.1152/jn.00510.2016
7.Sato F, Martinez NE, Shahid M, Rose JW, Carlson NG, Tsunoda I. Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. Am J Pathol. Nov 2013;183(5):1390-1396. doi:10.1016/j.ajpath.2013.07.006
8.Ramli I, Posadino AM, Giordo R, et al. Effect of Resveratrol on Pregnancy, Prenatal Complications and Pregnancy-Associated Structure Alterations. Antioxidants (Basel). Jan 31 2023;12(2)doi:10.3390/antiox12020341
9.Brawerman GM, Kereliuk SM, Brar N, et al. Maternal resveratrol administration protects against gestational diabetes-induced glucose intolerance and islet dysfunction in the rat offspring. J Physiol. Aug 2019;597(16):4175-4192. doi:10.1113/JP278082
10.Bourque SL, Dolinsky VW, Dyck JR, Davidge ST. Maternal resveratrol treatment during pregnancy improves adverse fetal outcomes in a rat model of severe hypoxia. Placenta. May 2012;33(5):449-52. doi:10.1016/j.placenta.2012.01.012
11.Roberts VH, Pound LD, Thorn SR, et al. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. Jun 2014;28(6):2466-77. doi:10.1096/fj.13-245472
12.Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. May 22 2002;50(11):3337-40. doi:10.1021/jf0112973
13.Hurst WJ, Glinski JA, Miller KB, Apgar J, Davey MH, Stuart DA. Survey of the trans-resveratrol and trans-piceid content of cocoa-containing and chocolate products. J Agric Food Chem. Sep 24 2008;56(18):8374-8. doi:10.1021/jf801297w
14.Rimando AM, Kalt W, Magee JB, Dewey J, Ballington JR. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem. Jul 28 2004;52(15):4713-9. doi:10.1021/jf040095e
15.Sanders TH, McMichael RW, Jr., Hendrix KW. Occurrence of resveratrol in edible peanuts. J Agric Food Chem. Apr 2000;48(4):1243-6. doi:10.1021/jf990737b
16.Creasey LL, Coffee, M. Phytoalexin production potential of grape berries. J Am Soc Hortic Sci. 1988;113(2):230-234.