Alzheimer’s disease (AD) is a devastating neurodegenerative disease which is linked with an inflammatory component. The receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation endproduct (AGE)-modified proteins and amyloid-β, which are elevated in AD brains, has been linked with increased neuroinflammation. This has led to our group’s search for anti-inflammatory natural product derived RAGE inhibitors (nRIs) as new pharmacological treatments of AD. The pomegranate (Punica granatum) fruit, a rich source of ellagitannins, has been reported by our group, and others, to exert anti-AD effects in animal models but the brain absorbable compounds are not known. Interestingly, while ellagitannins are not bioavailable in humans, they are biotransformed by gut microbiota into microbial metabolites, known as urolithins (dibenzopyranone derivatives) which achieve physiologically relevant concentrations and show anti-inflammatory effects in vivo. Therefore, given the above, we hypothesized that urolithins are the brain absorbable nRIs responsible for pomegranate’s protective effects against AD pathology. This hypothesis was supported by in silico (ACD/Labs to predict blood brain barrier penetration) and molecular docking (Autodock Vina to evaluate ligand-RAGE binding affinity) data. Using common motifs shared by known synthetic RIs, and functional group optimization, a library of urolithin derivatives was developed. Our group is currently pursuing ADMET, PK/PD, and further preclinical studies of these nRIs, and their related lead compounds, to advance their development as new anti-AD therapeutics. Also, this study underscores the importance of mining gut microbial metabolites, formed from host microflora metabolism of dietary natural products, for new therapeutic agents for chronic human illnesses including AD.

Natural product derived brain absorbable RAGE inhibitors for Alzheimer’s disease: The case of the urolithins

250th National Meeting (2015)

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