Secoisolariciresinol diglucoside (SDG), the main lignan in flaxseed, is known for its beneficial effects in inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes. SDG might be an attractive natural compound that protects against neuroinflammation. Yet, there are no comprehensive studies to date investigating the effects of SDG on brain endothelium using relevant in vivo and in vitro models.
We evaluated the effects of orally administered SDG on neuroinflammatory responses using in vivo imaging of the brain microvasculature during systemic inflammation and aseptic encephalitis. In parallel, the anti-inflammatory actions of SDG on brain endothelium and monocytes were evaluated in vitro blood-brain barrier (BBB) model. Multiple group comparisons were performed by one-way analysis of variance with Dunnet’s post hoc tests.
We found that SDG diminished leukocyte adhesion to and migration across the BBB in vivo in the setting of aseptic encephalitis (intracerebral TNFα injection) and prevented enhanced BBB permeability during systemic inflammatory response (LPS injection). In vitro SDG pretreatment of primary human brain microvascular endothelial cells (BMVEC) or human monocytes diminished adhesion and migration of monocytes across brain endothelial monolayers in conditions mimicking CNS inflammatory responses. Consistent with our in vivo observations, SDG decreased expression of the adhesion molecule, VCAM1, induced by TNFα, or IL-1β in BMVEC. SDG diminished expression of the active form of VLA-4 integrin (promoting leukocyte adhesion and migration) and prevented the cytoskeleton changes in primary human monocytes activated by relevant inflammatory stimuli.
This study indicates that SDG directly inhibits BBB interactions with inflammatory cells and reduces the inflammatory state of leukocytes. Though more work is needed to determine the mechanism by which SDG mediates these effects, the ability of SDG to exert a multi-functional response reducing oxidative stress, inflammation, and BBB permeability makes it an exciting potential therapeutic for neuroinflammatory diseases. SDG can serve as an anti-inflammatory and barrier-protective agent in neuroinflammation.
Zhang W, Wang X, Liu Y, Tian H, Flickinger B, Empie MW, Sun SZ. Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects. Br J Nutr. 2008;99:1301–9. PubMed
Cornish SM, Chilibeck PD, Paus-Jennsen L, Biem HJ, Khozani T, Senanayake V, Vatanparast H, Little JP, Whiting SJ, Pahwa P. A randomized controlled trial of the effects of flaxseed lignan complex on metabolic syndrome composite score and bone mineral in older adults. Appl Physiol Nutr Metab. 2009;34:89–98. CrossRefPubMed
Velalopoulou A, Tyagi S, Pietrofesa RA, Arguiri E, Christofidou-Solomidou M. The flaxseed-derived lignan phenolic secoisolariciresinol diglucoside (SDG) protects non-malignant lung cells from radiation damage. Int J Mol Sci. 2015;17:7.
Bernas MJ, Cardoso FL, Daley SK, Weinand ME, Campos AR, Ferreira AJ, Hoying JB, Witte MH, Brites D, Persidsky Y, et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood-brain barrier. Nat Protoc. 2010;5:1265–72. CrossRefPubMedPubMedCentral
Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, et al. Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosciences. 2012;32:4004–16.
Pietrofesa RA, Velalopoulou A, Albelda SM, Christofidou-Solomidou M. Asbestos induces oxidative stress and activation of Nrf2 signaling in murine macrophages: chemopreventive role of the synthetic lignan secoisolariciresinol diglucoside (LGM2605). Int J Mol Sci. 2016;17:322. CrossRefPubMedPubMedCentral
Ramirez SH, Heilman D, Morsey B, Potula R, Haorah J, Persidsky Y. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. J Immunol. 2008;180:1854–65. CrossRefPubMedPubMedCentral
Rom S, Fan S, Reichenbach N, Dykstra H, Ramirez SH, Persidsky Y. Glycogen synthase kinase 3beta inhibition prevents monocyte migration across brain endothelial cells via Rac1-GTPase suppression and down-regulation of active integrin conformation. Am J Pathol. 2012;181:1414–25. CrossRefPubMedPubMedCentral
Christofidou-Solomidou M, Tyagi S, Pietrofesa R, Dukes F, Arguiri E, Turowski J, Grieshaber PA, Solomides CC, Cengel KA. Radioprotective role in lung of the flaxseed lignan complex enriched in the phenolic secoisolariciresinol diglucoside (SDG). Radiat Res. 2012;178:568–80. CrossRefPubMedPubMedCentral
Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, Huber JD, O'Callaghan JP. Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience. 2010;170:633–44. CrossRefPubMedPubMedCentral
- Secoisolariciresinol diglucoside is a blood-brain barrier protective and anti-inflammatory agent: implications for neuroinflammation
Nancy L. Reichenbach
Michelle A. Erickson
Kelly L. Jordan-Sciutto
- BioMed Central