Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder of the cortex and hippocampus, which eventually leads to cognitive impairment. Although the etiology of AD remains unclear, the presence of β-amyloid (Aβ) peptides in these learning and memory regions is a hallmark of AD. Therefore, the inhibition of Aβ peptide aggregation has been considered the primary therapeutic strategy for AD treatment. Many studies have shown that resveratrol has antioxidant, anti-inflammatory, and neuroprotective properties and can decrease the toxicity and aggregation of Aβ peptides in the hippocampus of AD patients, promote neurogenesis, and prevent hippocampal damage. In addition, the antioxidant activity of resveratrol plays an important role in neuronal differentiation through the activation of silent information regulator-1 (SIRT1). SIRT1 plays a vital role in the growth and differentiation of neurons and prevents the apoptotic death of these neurons by deacetylating and repressing p53 activity; however, the exact mechanisms remain unclear. Resveratrol also has anti-inflammatory effects as it suppresses M1 microglia activation, which is involved in the initiation of neurodegeneration, and promotes Th2 responses by increasing anti-inflammatory cytokines and SIRT1 expression.
Despite the neuroprotective potential of resveratrol demonstrated in several in vitro studies, the major limitation currently facing is the lack of information from clinical studies that correlates the SIRT1 activation and the inflammatory and oxidative status reduction associated with improvement in the development and progression of AD. Overall, evidence from clinical trials is weak and largely inconclusive. Most human studies establish a link between consumption of foods rich in resveratrol and reducing the incidence or prevalence of AD, as well as improvement in learning, memory, visual and spatial orientation, and social behavior. However, these observed effects may be the result of complex direct and indirect interactions of the various constituents present in the diet, not only of resveratrol. In addition, other difficulties in clinical trials are the following: (i) the studies are mainly conducted with volunteers, not reflecting the target population, (ii) the participants’ age is quite broad between 18 and over 80 years of age, and (iii) sample size is rarely calculated and the slow progression of AD is not investigated because it requires longer clinical time in the trials. Another important issue is the poor bioavailability of resveratrol, which makes it difficult to link with the optimal concentrations achieved in in vitro experiments. Although preclinical studies also indicate that resveratrol is able to cross the blood-brain barrier, low concentrations of this molecule have been detected in the brain, and only higher concentrations of resveratrol and its metabolites have been found in the blood. In addition, it is emphasized that the neuroprotective effects of resveratrol are mainly short term, varying according to dose, dosage form, duration of treatment, pharmacokinetic and pharmacogenetic parameters, food and drug interactions, among others. Thus, we conclude that, to date, evidence based on clinical studies is still insufficient, contradictory, and inconclusive, so we recommend that further clinical trials be conducted to substantiate the neuroprotective effects of resveratrol and its likely mechanisms of action in the body. However, we emphasize that resveratrol is promising in health promotion, not only for its antioxidant activities but also for its anti-inflammatory and neuroprotective properties. Thereby, further studies assessing other routes of administration or pharmaceutical formulations (i.e., nanoencapsulation) are required to improve the tissue-targeting concentration and allow resveratrol to exert its biological activities in AD.
Resveratrol is a potential compound for the treatment of AD due to its antioxidant and anti-inflammatory properties. The key neuroprotective mechanism of resveratrol in AD seems to be linked with SIRT1 activation. Although the mechanisms that link resveratrol to the overexpression of SIRT1 and neuroprotection are unknown, this expression may play an important role in neuronal protection from ROS, NF-κB signaling in activated microglia, prevent Aβ toxicity, and contribute to improved learning and memory function. Resveratrol can also effectively suppress the apoptotic activities of both p53 and FOXO via SIRT1 overexpression and confer neuronal protection in AD. Although this review focuses on the importance of SIRT1 activation for the neuroprotective role of resveratrol, it is also important to clarify that these mechanisms are still unclear and fully elucidated. In addition, resveratrol may act on CNS by inhibiting neuroinflammatory and prooxidant mechanisms by multiple action mechanisms that are independent of SIRT-1. These mechanisms are quite complex and involve stimulation or inhibition of multiple signaling pathways or alteration of potassium channels eading to inhibition of neuronal electrical activity. In summary, the major mechanisms that may be associated with the neuroprotective effect of resveratrol, in addition to SIRT1, include stimulation of regulation by microRNA-CREB-BDNF pathway, inhibition of mTOR and AMPK-dependent signaling pathways, inhibition of enzymes (cholinesterase activity), transcription factor (NF-κB) and apoptotic pathways, and stimulation of cellular autophagy and expression of Nrf2, HO-1, NQO1, among others. Therefore, we critically analyze and suggest that SIRT1 is one of the main mechanisms related to the beneficial effects of resveratrol; however, this compound can change multiple pathways simultaneously, and then, there is a need for crosstalk between signaling and regulatory functions to provide improvements in the development and progression of AD. In addition, caution is required in therapies with natural products, since intrinsic aspects of the patient, environmental factors, and characteristics of the compound studied are important for efficacy and therapeutic success.