Phytosterols
Phytosterols, also called plant sterols, are a group of naturally occurring compounds found in plant cell membranes. Associated primarily with lowering cholesterol levels, some have been shown to possess important antioxidant and anti-inflammatory effects relevant to neuroinflammation in neurodegeneration1-3.
In the EAE animal model of MS, phytosterols (a mixture of β-sitosterol, campesterol, and stigmasterol) were shown to protect against development of disease by reducing infiltration and inflammatory activity of immune cells (including macrophages) into the CNS, thereby decreasing associated demyelination4.
In another EAE study, treatment with the phytosterol withametelin in doses of 10, 100, and 1000 mcg/kg prior to disease induction markedly inhibited oxidant-induced cellular toxicity and oxidative stress in a dose-dependent manner (meaning the higher the dose, the bigger the effect). Post disease treatment significantly improved clinical score, weight loss, neuropathic pain, and movement dysfunction, as well as circulating leucocytes, spinal deformity, and splenomegaly (pathologic enlargement of the spleen). This significant neuroprotective potential in appeared to be via modulation of Nrf2 mediated-oxidative stress and NF-κB mediated inflammation5. Withametelin is isolated from the leaves of the Datura metel plant (native to India), also known as Indian Thornapple, Hindu Datura, Devil’s Trumpet, and Angel’s Trumpet.
In animals with neuroinflammation induced by the bacterial toxin lipopolysaccharide, beta-sitosterol treatment at doses of 3.3 and 6.6 mg/day (equivalent to several grams in humans) was shown to reduce inflammatory mediators (including interleukin-6 (IL-6), inducible nitric oxide (iNOS), tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 (COX-2) in microglial cells, without toxicity3.
Phytosterol supplementation in pregnant and/or lactating animal models demonstrated safety at high doses of 2% of food intake6,7, equivalent to several grams in humans, exceeding the doses found to have neurological benefits3,5. In a human study, 2 g/day of phytosterol supplementation in pregnant woman was associated with reduced complications in newborns8.
Beta-sitosterol is widely found in foods such as rice bran, wheat germ, avocados, nuts, seeds, canola and corn oils, and soybeans9.
References
1.Dash R, Mitra S, Ali MC, et al. Phytosterols: Targeting Neuroinflammation in Neurodegeneration. Curr Pharm Des. 2021;27(3):383-401. doi:10.2174/1381612826666200628022812
2.Sharma N, Tan MA, An SSA. Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases. Int J Mol Sci. Nov 12 2021;22(22)doi:10.3390/ijms222212255
3.Sun Y, Gao L, Hou W, Wu J. beta-Sitosterol Alleviates Inflammatory Response via Inhibiting the Activation of ERK/p38 and NF-kappaB Pathways in LPS-Exposed BV2 Cells. Biomed Res Int. 2020;2020:7532306. doi:10.1155/2020/7532306
4.Valerio M, Liu HB, Heffner R, et al. Phytosterols ameliorate clinical manifestations and inflammation in experimental autoimmune encephalomyelitis. Inflamm Res. May 2011;60(5):457-65. doi:10.1007/s00011-010-0288-z
5.Khan A, Shal B, Khan AU, et al. Withametelin, a novel phytosterol, alleviates neurological symptoms in EAE mouse model of multiple sclerosis via modulation of Nrf2/HO-1 and TLR4/NF-kappaB signaling. Neurochem Int. Dec 2021;151:105211. doi:10.1016/j.neuint.2021.105211
6.Dumolt JH, Radhakrishnan SK, Moghadasian MH, et al. Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation. J Nutr Biochem. Feb 2018;52:10-17. doi:10.1016/j.jnutbio.2017.09.013
7.Rideout TC, Movsesian C, Tsai YT, Iqbal A, Raslawsky A, Patel MS. Maternal Phytosterol Supplementation during Pregnancy and Lactation Modulates Lipid and Lipoprotein Response in Offspring of apoE-Deficient Mice. J Nutr. Aug 2015;145(8):1728-34. doi:10.3945/jn.115.215061
8.Gao F, Wang G, Wang L, Guo N. Phytosterol nutritional supplement improves pregnancy and neonatal complications of gestational diabetes mellitus in a double-blind and placebo-controlled clinical study. Food Funct. Jan 25 2017;8(1):424-428. doi:10.1039/c6fo01777k
9.Pizzorno JE, Murray, M.T., Joiner-Bey, H. Benign prostatic hyperplasia. The Clinician’s Handbook of Natural Medicine, Third Edition. Elsevier; 2016:137-146.