Key findings
In the current study, SDG oral administration in order to diminish neuroinflammation and BBB injury in relevant animal models including aseptic encephalitis induced by intracranial (i.c.) injection of TNFα was assessed. Oral administration of SDG attenuated leukocyte adhesion and migration across the BBB. BBB injury is documented in multiple neuroinflammatory disorders (multiple sclerosis, viral encephalitis) and neurodegenerative processes (Alzheimer’s and Parkinson’s diseases). It plays a role in neuronal dysfunction due to changes in the unique environment of the CNS. Identification of effective anti-inflammatory, non-toxic barrier-protective compounds is therefore of paramount importance. SDG administration (100 mg/kg twice daily) diminished adhesion and migration by 50 and 64%, respectively. To explore the mechanisms of the anti-inflammatory SDG effects, the expression of VCAM-1 after stimulation with TNFα or IL-1β was assessed. Enhanced expression of VCAM-1 (2.3- and 4-fold, respectively) was decreased by 33–35% by SDG suggesting that VCAM reduction could be one of the factors in attenuated adhesion and migration after SDG treatment. Protective properties of SDG could also be attributed to anti-inflammatory effects on leukocytes in addition to brain endothelium.
SDG has been shown to mitigate pathology in several disease models where oxidative stress and inflammation play a prominent role, including atherosclerosis, diabetes, lung disease from radiation exposure, liver and kidney diseases. This study suggests that SDG directly inhibits BBB interactions with inflammatory cells while also reducing the inflammatory state of leukocytes. Although more work is needed to determine the mechanism by which SDG mediates these effects, the potential ability of SDG to exert a multi-functional response to reduce oxidative stress, inflammation, and BBB permeability make it an exciting potential therapeutic for neuroinflammatory diseases. SDG may serve as an anti-inflammatory and barrier-protective agent in neuroinflammation.
ABSTRACT
BACKGROUND: 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. METHODS:
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.
RESULTS: 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.
CONCLUSION: 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.