Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet.

Michel Bernier,Shakeela Faulkner,Zsuzsanna Tucsek,Artur Wnorowski,Irene Alfaras,Rafael De Cabo,Kevin J Pearson,Devin Wahl,Ahmed Ali,Julie A Mattison,Mitesh Sanghvi,Zoltan Ungvari,Joanne Allard,Stefano Tarantini,Anna Csiszar,Ruin Moaddel

doi:10.18632/aging.100942

Abstract

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress.

Highlights

Worldwide incidence of obesity is at an all-time high, with more than 1.1 billion adults being classified as overweight or obese
No attempts were made to identify metabolites of RSV; we previously reported the detection of RSV and resveratrol-3-O-sulfate in the serum of HFS supplemented with RSV (HFS+R)-fed animals, but not of resveratrol-4’O-glucuronide nor 3-O-glucuronide, which were below the minimum quantitation limits [30]
Whole genome microarray analysis was performed on cerebral cortex tissues of middle-aged male rhesus monkeys fed for two years either with standard diet (SD), HFS or HFS+R diet

Summary

Introduction

Worldwide incidence of obesity is at an all-time high, with more than 1.1 billion adults being classified as overweight or obese. High-fat diet has been associated with central inflammation, brain insulin resistance, and cognitive decline leading to progressive neurodegeneration [3], and resveratrol (RSV; 3, 4’, 5trihydroxy-trans-stilbene) supplementation can attenuate central inflammation and improve memory deficits in HFD-fed mice [4]. Since 1940, RSV has generated considerable interest in the scientific community due to its ability to protect against a variety of diseases, including type-2 diabetes, cardiovascular disease, and cancers [5]. RSV improves endothelial function and cerebral vascular density [12, 13] by increasing levels of vascular endothelial growth factor (VEGF) [14], which enhances angiogenesis [15] and attenuates ischemic brain damage [16]

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