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

Article type: Research Article

Authors: Dennison, Jessica L.^{a; b} | Volmar, Claude-Henry^{a; b; *} | Modarresi, Farzaneh^{a; b} | Ke, Danbing^c | Wang, James^c | Gravel, Emilie^d | Hammond-Vignini, Sabrina^d | Li, Zuomei^d | Timmons, James A.^e | Lohse, Ines^{a; b} | Hayward, Marshall A.^f | Brothers, Shaun P.^{a; b} | Wahlestedt, Claes^{a; b; *}

Affiliations: [a] Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA | [b] Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA | [c] KDM Laboratories Inc., Montreal, QC, Canada | [d] NuChem Sciences Inc., St. Laurent, QC, Canada | [e] Augur Precision Medicine LTD, Stirling, UK | [f] Jupiter Neurosciences, Inc. Jupiter, FL, USA

Correspondence: [*] Correspondence to: Claes Wahlestedt, MD, PhD, and Claude-Henry Volmar, PhD, Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA. E-mails: [email protected] and [email protected].

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-229006, available at http://doi.org/10.3233/JAD-229006.

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, JOTROL™, 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.

Keywords: Alzheimer’s disease, inflammation, neuroprotection, resveratrol, sex differences

DOI: 10.3233/JAD-215370

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 173-190, 2022