Resveratrol and cognitive decline: a clinician perspective

Abstract

Resveratrol (3,5,4'-trihydroxystilbene) belongs to a family of polyphenolic compounds known as stilbenes, particularly concentrated in grape and red wine. The aim of our review was to critically review the available evidence of resveratrol effects on brain function and its potential impact on therapy. In preclinical models of cognitive decline, resveratrol displays potent antioxidant activity by scavenging free radicals, reducing quinone reductase 2 activity and upregulating endogenous enzymes. Resveratrol also inhibits pro-inflammatory enzyme expression, reduces nuclear factor-κB activation and cytokine release. Treatment with resveratrol can affect multiple signaling pathway effectors involved in cell survival, programmed cell death and synaptic plasticity. Direct and/or indirect activation of the deacetylase sirtuins by resveratrol has also been suggested. In humans, clinical evidence derived from randomized clinical trials suggests that resveratrol is able to improve cerebral blood flow, cerebral vasodilator responsiveness to hypercapnia, some cognitive tests, perceived performances, and the Aβ₄₀ plasma and cerebrospinal fluid level.

Keywords: clinical trials; cognitive function; neuroprotection; preclinical models; resveratrol.

Figure 1

Summary of the neuroprotective action of resveratrol. Resveratrol displays potent antioxidant activity by scavenging free radicals and metals, protecting against NO toxicity, reducing QR2 activity and upregulating endogenous enzymes such as glutathione peroxidase, AMPK and LKB1. Resveratrol also inhibits pro-inflammatory enzyme (i.e., COX-1 and -2) expression, reduces NF-κB activation as well as PGE2, NO, and TNF-α production, and cytokine release. It may promote Aβ clearance. Treatment with resveratrol can affect multiple signaling pathway effectors involved in cell survival (AMPK, PI3-k and AkT), programmed cell death (caspase-3/12, Bax, and cytochrome c) and synaptic plasticity (ERK1/2). Direct and/or indirect activation of the deacetylase sirtuins by resveratrol has also been suggested. AMPK – AMP-activated protein kinase, COX – cyclooxygenase, ERK – extracellular signal-regulated kinase-1 and -2 (ERK1/2), LKB1 – liver kinase B1, NF-κB – nuclear factor κB, NO – nitric oxide, PGE2 – prostaglandin E2, PI3-k – phosphoinositide 3-kinase, QR2 – quinone reductase 2. Reproduced with permission of Elsevier [29].