Project Summary Resveratrol has shown potential therapeutic utility in a number of disorders characterized by neuronal degradation, mitochondrial dysfunction, inflammation, and the presence of reactive oxygen species. Resveratrol has shown beneficial outcomes in Alzheimer’s Disease (AD). Resveratrol use is limited by poor bioavailability due to rapid and extensive first pass metabolism. At doses that correlate with positive disease outcomes, gastrointestinal intolerability is an issue. A high bioavailability orally administered resveratrol (JOTROL) has been developed, and a patent protecting the formulation and utility has been granted. The US FDA has authorized a single ascending dose pharmacokinetic (PK) study with food effect in order to establish dosing regimens in several proposed phase 2 clinical studies, including AD. A PK study of JOTROL is a necessary enabling trial to allow a Phase 2 study in AD, the premise of the current project. Resveratrol has previously been evaluated in AD clinical trials and evidence of a positive response with respect to Alzheimer’s biomarkers and CNS inflammation has been reported. Additionally, resveratrol has a number of pharmacologic activities that are identified as potential targets for AD. Resveratrol is a sirtuin activator (SIRT1 deacetylates histones and non-histone proteins such as transcription factors); stimulates mitochondrial biogenesis; has CNS and systemic anti-inflammatory properties; improves neuronal function; and scavenges reactive oxygen species. In a phase 2 AD study, resveratrol demonstrated stabilization of key biomarkers, including amyloid levels in CSF and plasma. Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini- mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels. Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. Study associated population PK data show the attained plasma level in this study was too low to generate a maximal therapeutic effect of resveratrol treatment. The poor bioavailability of resveratrol due to extensive and rapid first pass liver metabolism limits utility. In all cases where biomarkers and/or clinical efficacy is observed in response to resveratrol, it is only at very high doses associated with GI intolerability. The levels of circulating resveratrol are in the range that is expected to be required to elicit the full beneficial effects of resveratrol, i.e., approximately...