Abstract
BackgroundEmerging evidence suggests that disturbances in the blood–brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders. Studies suggest that heightened systemic and central inflammations are associated with BBB dysfunction. This study investigated the effect of the anti-inflammatory nutraceuticals garlic extract-aged (GEA), alpha lipoic acid (ALA), niacin, and nicotinamide (NA) in a murine dietary-induced model of BBB dysfunction.MethodsC57BL/6 mice were fed a diet enriched in saturated fatty acids (SFA, 40% fat of total energy) for nine months to induce systemic inflammation and BBB disturbances. Nutraceutical treatment groups included the provision of either GEA, ALA, niacin or NA in the positive control SFA-group and in low-fat fed controls. Brain parenchymal extravasation of plasma derived immunoglobulin G (IgG) and large macromolecules (apolipoprotein (apo) B lipoproteins) measured by quantitative immunofluorescent microscopy, were used as markers of disturbed BBB integrity. Parenchymal glial fibrillar acidic protein (GFAP) and cyclooxygenase-2 (COX-2) were considered in the context of surrogate markers of neurovascular inflammation and oxidative stress. Total anti-oxidant status and glutathione reductase activity were determined in plasma.ResultsBrain parenchymal abundance of IgG and apoB lipoproteins was markedly exaggerated in mice maintained on the SFA diet concomitant with significantly increased GFAP and COX-2, and reduced systemic anti-oxidative status. The nutraceutical GEA, ALA, niacin, and NA completely prevented the SFA-induced disturbances of BBB and normalized the measures of neurovascular inflammation and oxidative stress.ConclusionsThe anti-inflammatory nutraceutical agents GEA, ALA, niacin, or NA are potent inhibitors of dietary fat-induced disturbances of BBB induced by systemic inflammations.
Highlights
Emerging evidence suggests that disturbances in the blood–brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders
We investigated the efficacy of selected anti-oxidative nutraceuticals, namely garlic extract-aged (GEA), alpha-lipoic acid (ALA), niacin, and nicotinamide (NA), in an established dietary-induced model of BBB disruption
The total calories consumed were approximately equivalent for the mice maintained on LF control chow and high saturated fat (SFA) diet, and a similar weight gain was recorded in most treatment groups for a nine-month intervention period (Table 1)
Summary
Emerging evidence suggests that disturbances in the blood–brain barrier (BBB) may be pivotal to the pathogenesis and pathology of vascular-based neurodegenerative disorders. Accumulating evidence suggests that disturbances in cerebral capillary integrity characterized by inflammation, loss of blood–brain barrier (BBB) functions, parenchymal extravasation of plasma proteins, proteinaceous deposits on extracellular matrices, and glial cell activation contribute to the onset or progression of a number of neurodegenerative disorders including vascular dementia, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis [1]. Cerebral capillary dysfunction induced as a consequence of a chronically heightened state of systemic inflammation is positively associated with neurovascular degenerative disorders [6,7,8,9] Comorbidities such as dyslipidemia, hypertension or endocrine disorders, exposure to pollutants such as smoking, alcohol consumption, or atherogenic diets may increase neurodegenerative disease onset via a cerebral capillary axis [3,6,8,9,10]. Wild-type mice chronically fed pro-inflammatory diets enriched in saturated fatty acids (SFA) or cholesterol showed hallmark features of BBB dysfunction including cerebral extravasation of large plasma proteins (immunoglobulin G (IgG) and macromolecules (apolipoprotein (apo) B lipoproteins)) concomitant with diminished endothelial tight junction proteins [9,11,12,13]
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