JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model1

Abstract

Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROLTM, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Sexual dimorphism in the context of nutrition and health

“…HPLC-MS/MS analysis of acute doses of grape seed (poly)phenols established clear sex differences in the metabolism and distribution of flavanols throughout the bodies of rats, with quantitative differences found in the plasma and brain (99) . In line with this supplementation with an oral formulation of resveratrol, JOTROL™ in 3xTg-AD mice resulted in Alzheimers disease (AD)-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain regiondependent and sex-specific (100) . Analysis of the Primary prevention of cardiovascular disease with a mediterranean diet (PREDIMED) study revealed that catechins, proanthocyanidins, hydroxybenzoic acids and lignans were inversely associated with type 2 diabetes, with women displaying stronger inverse associations.…”

Hub Genes, Diagnostic Model, and Predicted Drugs Related to Iron Metabolism in Alzheimer's Disease

“…Deuterated dextromethorphan/quinidine (AVP-786) is a promising and well-tolerated treatment option for agitation in AD, having completed two phase III trials (Garay and Grossberg, 2017 ; Khoury et al, 2021 ; Khoury, 2022 ). Resveratrol (DB02709), a polyphenolic phytoalexin, has been reported to affect several AD-related- and neuroprotective genes (Dennison et al, 2022 ). Resveratrol can improve AD-associated pathologies and produce therapeutic effects (Gomes et al, 2018 ; Rahman et al, 2020 ; Yan et al, 2020 ; Fang et al, 2021 ; Gu et al, 2021 ; Jang et al, 2021 ; Abozaid et al, 2022 ).…”

Low-Dose Chidamide Treatment Displays Sex-Specific Differences in the 3xTg-AD Mouse

“…A series of behavior tests intended to test motor coordination, anxiety, spatial learning, and reference memory was performed as previously performed by our lab [ 19 ]. Motor coordination was assessed at 11 months of age using rotarod.…”