The Anxiety and Depression Association of America estimated that nearly 16 and 40 million people, respectively, in the United States suffer from depression and anxiety. Therefore, finding stable and effective (if natural even better) molecular options for these medical conditions, may represent a viable avenue of natural treatment. Resveratrol is a natural non-flavonoid polyphenol found abundantly in the skins and seeds of berries and grapes and, of course, in red wine, which has numerous pharmacological properties including antioxidant, anti-stress and antidepressant-like abilities. There is some discrepancy between the effects of reseveratrol as a drug and as a possible modulator of brain or heart health. Original studies indicated a protective effects of reseveratrol in the range of 1-5 mg, that is the amount of the substance present in a meal with most of foods enriched with. Other indipendent lab studies found other biological effects by employing doses in the 20-200mg range. It is unlikely that such doses may be reached by regular daily meals; this could, however, partially be done with supplements.
But are there proofs that reseveratrol could help handling depression and/or anxiety?. A recent study by a scientist team from Xinxiang Medical University published in 2018 explored the therapeutic effects of resveratrol on mice with depression. They selected lab rats with an induced depression and divided them into groups: the model group, the low dose, the medium dose, the high dose group and the control group. The rats in the low, medium and high dose groups were given injections of resveratrol 10, 20 and 30 mg/kg, respectively. The control and model groups received placebo. After a treatment for 21 days tests revealed reduction in depression and brain tests showed that there was a rise in brain dopamine and serotonin level – the indicators of depression. There was also a significant rise in Neuropeptide Y expression in the brain in rats treated with resveratrol. The team concluded that resveratrol can significantly increase the levels of neurotransmitters DA and 5-HT in the prefrontal cortex and increase the expression of NPY in the brain, which can play an antagonistic role in depression.
According to scientists, resveratrol may be an effective alternative to drugs for treating patients suffering from depression and anxiety disorders. This compound specifically played a role in the enzyme phosphodiesterase 4 (PDE4) which in turn is influenced by the stress hormone corticosterone. The PDE4 enzyme is capable of lowering the cyclic adenosine monophosphate or cAMP in the brain which is a messenger that causes signalling of several physiological processes including cell division, movement and neurotransmitters actions. Alteration of the PDE4 and cAMP in the brain led to alterations in the structure of the brain. Hormones cortisol or corticosterone is released in the body as a response to stress and excess stress can trigger excess release of the hormone that reaches the brain and leads to depression and anxiety. At present the treatment for depression and anxiety focuses on serotonin or noradrenaline – neurotransmitters in the brain. But it is known that one in three patients with depression and/or anxiety disorders benefit from the drug modulating the neurotransmitters and reach full remission.
For their study the team used lab mice on which they showed that PDE4 in the brain was influenced by the excess cortisol released as a response to stress. This led to anxiety and depression related symptoms in the mice. The team investigated both in vivo and in vitro effects of resveratrol and noted that a specific region of the brain called the hippocampus was altered by the increase in the PDE4 expression, that led to the anxiety and depression-like behaviour in the mice. They noted that using only 100 μM final concentration of corticosterone, they could induce isoforms of PDE in the mice brain called PDE2A, PDE3B, PDE4A, PDE4D, PDE10 and PDE11. Not all these isoforms act on cAMP; some others influnece another nucleotide called cGMP, which is implicated in memory and learning in specific brain areas, like the cerebellum. Corticosterone led to neuronal degeneration, but when treated with resveratrol the cells became more viable and with rising dose of the compound the cell viability rose, the researchers explained. PDE4D expression was specifically affected by resveratrol.
The team found that resveratrol could help reverse these effects and showed a neuroprotective effect in the brain by working against the damage caused by corticosterone. The compound successfully inhibited the expression of PDE4, most likely acting on inner signaling mechamisms. The researchers concluded that resveratrol-induced antidepressant- and anxiolytic-like effects are mediated by PDE4D enzyme. Overall, these findings support the hypothesis that PDE4D-mediated cAMP signaling plays an important role in resveratrol’s protective effects on stress-induced depression- and anxiety-like behaviors. Another team in 2019 discovered that resveratrol treatment od Alzheimer mice model enhanced the expression of the glutamate NMDAR receptor in the brain hippocampus, aling with one of its signaling component, the protein kinase C (PKC) involved in neural plasticity and cognition. The fact that resveratrol may affect the expression of proteins involved in cognition, originally led scientists to deem anxiety, depression or cognitive decline as disturbances in mood learning.
Parallel studies implicated an influence of resveratrol on the cellular antioxidant system and its condition upon depression or anxiety. This has a rationale, since ever more researches demonstraed that oxidative stress lies beneath the neuronal disfunction of brain cells in depression and axìnxiety as well. Resveratroli is antioxidant itself; however, it is highly unlikely that a couple of milligrams would exert such an action in a human adult. Resveratrol is known to have molecular targets, lìke the estrogen receptor (ER-alpha) and enzymes called sirtuins (e.g. SIRT1), which can affect gene expression inside cells. There is also proof that resveratrol activates a signaling pathway which lead to Nrf-2. This cellular sensor is a transcrption factor resting in the cytoplasm assembled with an inhibitor (Keap-1). When oxidants (ROS), heavy metals or chemopreventive substances like polyphenols and resveratrol itself allow Keap-1 to detach from Nrf-2, this transcription factor is free to move inside cell nucleus and activate a specific gene response comprising proteins and enzymes antagonizing oxidative stress (e.g. TxR1, GST-1, SOD2, etc.).
Reseveratrol may as well affect cyclo-oxigenase 2 (COX2), the inflammatory enzyme target of common NSAIDs like ibuprofen or celecoxib. As said earlier, however, the amount of resveratrol to affect the enzyme would be even higher than NSAIDs themselves, since its specificity toward COX2 is not so high. Therefore, it is probable that protective effects of resveratrol with diet would exert through this last mechanisms, rather than with other conventional signaling pathways. Diet is known form epigenetics and pharmacology to affect directly many aspects of human biology, form behavior to immunity. Latest data from the “microbiota” world prove that diet influence microbial composition in the gut, leading to direct effects on our metabolism, immune response and even neurochemistry. It is very recent the notion how resveratrol may imporve the dialogue gut-brain in a model of irritable bowel syndrome, by influencing neurotransmitters like serotonin (5-HT), gamma-aminobutyrate (GABA) and dopamine.
Microbiota is now become a central actor in the coordination of human brain health; hundreds of publications prove that bacterial metabolism and its inlfuence on the local immune system, are able to directly and indirectly our brain chemistry. This means neurotransmitters and antioxidant defences as well, which once undergo weakening they will open the door to oxidative stress and neuroanl malfunctiong that reveal themselves as depression adn/or anxiety. These notions are strenghtening the relationship between our daily diet with metabolism, mental wellbeing and general health.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Griñán-Ferré C et al. Ageing Res Rev. 2021; 67:101271.
Shayganfard M. Cell Bioscience 2020 Nov 7; 10(1):128.
Zhu X et al. Neuropharmacology 2019 Jul 15; 153:20-31.
Liu T et al. Psychopharmacology 2019; 36(4):1385-1399.
Kong D et al. Biomed Res Int. 2019 Mar; 2019:8983752.
Yu YC, Li J et al. Front Cell Neurosci. 2019 Feb; 13:30.
Zhang Y et al. Wei Sheng Yan Jiu 2019; 48(2):269-278.
Wang F et al. Mol Med Rep. 2018 Mar; 17(3):4611-4618.
Solanki N et al. Int J Neuropsychopharm. 2017; 20(7):550.