Biologically relevant secondary metabolites of Vaccinium uliginosum: Bioassay-directed natural products identification of anti-neuroinflammatory agents in the Alaska bog blueberry

Dietary blueberry supplementation has demonstrated numerous health benefits including improved learning and memory in aging and neurodegenerative models, neuroprotection from ischemic events, anti-diabetic properties, and modulation of multiple inflammatory cascades Despite previous research on antioxidant components prevalent in blueberries, no adequate explanation for a molecular mechanism for the benefits of blueberry supplementation has been proposed. Vaccinium uliginosum, the Alaska bog blueberry, possesses higher concentrations of antioxidant components than commercial varietals, and exhibits a greater oxygen radical scavenging capacity, making it an excellent candidate for the identification of biologically relevant secondary metabolites. An approach of bioassay-directed natural products identification was utilized to identify compounds in the Alaska bog blueberry responsible for the inhibition of both a magnesium-dependent neutral sphingomyelinase and NADPH oxidase in TNF-alpha-induced SH-SYSY human neuroblastomas. Five relevant metabolites were identified: beta-sitosterol (1), ursolic acid (2), 3-0-(4-hydroxyphenylcarboxylic acid) 4-0-(beta-D-glucopyranosyl) gallic acid (3), malic acid (4), and 2,3-dihydroxybutane-1,2,3,4-tetracarboxylic acid ( 5). Neither compounds 3 or 5 had been previously described as a natural product in the literature. The identification of these compounds in the Alaska bog blueberry provides new explanations as to the benefits of blueberry consumption and offers new avenues of research for nutraceutical treatment of neuroinflammation.