Resveratrol: from plants to mammal brain-targeting
Many natural components of diet have been investigated in recent years, in particular the antioxidants that have been shown to cause numerous biological effects in different cell types and tissues.1–3 The redox active compound resveratrol (3,4′,5-trihydroxy-trans-stilbene) is one of the most studied antioxidants; it was first found in roots of white hellebore and later in roots of Polygonum cuspidatum.4 In plants, resveratrol is a phytoalexin found mainly in grapes, grape juice, wine, and berries.5,6 In ancient medicine Hippocrates made observations on the medicinal properties of wine; Galen also reported that preparations of wine and herbs could be used as antidotes to poisons.7 Today, red wine has gained particular attention especially owing to the French paradox that describes, particularly in southern France, an inverse correlation between intake of a diet rich in lipids (and wine) and a low incidence of heart disease.8–10 Among the wines with the highest concentration of resveratrol, wines from the south of Brazil stand out; due to the high humidity of the soil, they naturally have a higher amount of the phytoalexin resveratrol.11
Since the first reported detection of resveratrol in grapevines in 1976, a plethora of beneficial effects have been described in mammals, including cardioprotective, chemopreventive, and anti-inflammatory activities.5,6,10,12–15 Many papers locate the most diverse actions of resveratrol in its direct antioxidant and scavenger effects or by its ability to modulate and improve cellular antioxidant defenses.6,13 One of the signaling pathways modulated by resveratrol is that of the sirtuin protein family (SIRT1–7 in mammals). This is a conserved family of NAD+-dependent deacetylases (class III histone deacetylases) that exerts effects related to lifespan extension in diverse species.16 In mammalian cells, resveratrol induces SIRT1-dependent effects that are consistent with improved cellular function and implicated to play a role in a number of age-related human diseases. The effects of resveratrol on sirtuins may explain its positive effect on longevity.13,17
As mentioned, the central nervous system (CNS) is a target of resveratrol because this polyphenol can pass the blood–brain barrier.18 Among resveratrol's neuroprotective roles are benefits described in animal models of Alzheimer's and Parkinson's diseases19 and ischemia.20
Resveratrol, oxidative stress, and brain pathology
From epidemiological studies, resveratrol is recognized as a component that offers many health benefits: it may protect cell constituents against oxidative damage and, therefore, limit the risk of diseases such as atherosclerosis and cancer by directly acting on reactive oxygen species (ROS) or by stimulating endogenous defense systems.6,9,21–23 Oxidative stress has strong implications for many human diseases and has been connected with neurodegenerative disorders.24 Brain cells have the capacity to produce peroxides, particularly hydrogen peroxide (H2O2), in large amounts.25 H2O2 concentrations of up to 100 μM have been reported for brain in a microdialysis study.26 In this context, the defense of glial cells against peroxide-mediated oxidative damage would likely be essential for maintaining brain functions.
The last 25 years have seen an exponential increase in knowledge of the neuroglial plasticity.27 Astroglial cells have been implicated in numerous ways in brain metabolism, especially by the fact as they influence neuronal function, particularly at the level of synapses.27–31 Numerous studies demonstrated that astrocytes play a significant role in neurodegenerative disorders32–34 and exert a fundamental protective function against oxidative stress because of their effects on the metabolism of the antioxidant glutathione (GSH) and the defence against ROS.35
Primary astrocytes and C6 astroglial cell cultures are good models to study glial function, signaling pathways, and mechanisms of peroxide disposal by brain cells.36–41 In such cultures, however, the influence of other types of brain cells on the antioxidant potential is lacking, in contrast to the in vivo situation. Nevertheless, in spite of the fact that comparison of the in vitro results with the in vivo condition is limited, mainly because astrocyte cells in cultures are two-dimensional and the astroglia in situ exist in a three-dimensional matrix, an enormous amount of molecular information has been learned from the study of astroglial cultures (primary and lineage cells), particularly as pertains to the molecular mechanisms that underlie glutamate metabolism, much of which is applicable in vivo.
Glutamate is the major excitatory neurotransmitter in the CNS and plays an important role in neural plasticity and neurotoxicity.42 The modulation of extracellular glutamate determines its physiological and excitotoxic actions. The main mechanism responsible for the maintenance of low-extracellular concentrations of glutamate is performed by a family of glutamate transporter proteins, which use the electrochemical gradients across the plasma membranes as driving forces for uptake.27 In astrocytes, glutamate is converted into glutamine by the enzyme glutamine synthetase (EC 188.8.131.52).43 Glutamine is released by astrocytes and taken up by neurons to be again converted to glutamate; this system is called glutamate–glutamine cycle.44 The interaction between presynaptic and postsynaptic neurons together with astrocytes characterizes the tripartite synapse.45 Glutamate uptake is also important for maintaining levels of GSH, the major antioxidant of the brain. GSH is a tripeptide formed by amino acids cysteine, glutamate, and glycine, where the sulfhydryl group (SH) of cysteine serves as a proton donor and is responsible for the biological antioxidant effect of GSH.44 Moreover, GSH secreted from astrocytes serves as the basis for the synthesis of GSH neuronal.43,46 A large variety of neurological and psychiatric disorders, including depression, anxiety disorders, schizophrenia, chronic pain, epilepsy, and Alzheimer's and Parkinson's diseases, demonstrate pathophysiology impairments in the glutamatergic system.47