Neuroprotective effects of resveratrol in Alzheimer disease pathology.

The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol, with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occur mainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alter this significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronides and sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknown products, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism include the intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought. Deconjugation enzymes such as β-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol, may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improved bioavailability, may be important in future research. © 2011 New York Academy of Sciences.