Resveratrol is a natural polyphenol present in more than seventy plant species and can also be extracted from red grapes in the process of making red wine.

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Resveratrol

Resveratrol has several potential health benefits. Researchers have studied the potential of resveratrol to reduce cardiovascular disease and act as an anticancer drug, antiviral treatment, and an anti-inflammatory drug.

However, despite promising results from preliminary studies, clinical trials still need to be carried out to confirm the efficacy and safety of resveratrol. Recent research has shown that resveratrol can have a potential anti-stress effect by blocking the expression of an enzyme that is associated with the control of stress.

Thus, resveratrol is considered a potential candidate for the development of treatments for anxiety and depression.

Major depressive disorders are serious psychiatric illnesses that are characterized by high comorbidity of anxiety, mood disorders, and depression. These burdensome illnesses are a major cause of lost years of a healthy life.

The unknown etiopathology of MDD accounts for the complexity of pharmacotherapy. Research has yielded evidence showing that sustained stress or excessive secretion of stress hormone leads to the dysfunction of the hypothalamic-pituitary-adrenal axis (HPA-A). The brain undergoes a series of cellular and molecular alterations that cause maladaptive remodeling and behavioral abnormalities.

Stress protection

Resveratrol is a compound found in many plant species including the skin and seeds of grapes and berries. It is related to phosphodiesterase 4 (PDE4) which is an enzyme that is influenced by corticosterone, also known as the stress hormone. This hormone regulates the body’s response to stress.

Extreme stress leads to an excessive amount of corticosterone released in the brain which is the cause of mental disorders such as anxiety and depression. Current anti-depressant medication focuses on modulating serotonin and noradrenaline pathways in the brain.

However, this treatment is not always effective in patients with depression. This means that there is a growing demand for the development of new medication for this condition.

Studies have suggested the depression-alleviating properties of resveratrol in rats. The most recent study to explore the properties of resveratrol using the animal model was conducted by Zhu and colleagues. The research demonstrated that excessive amounts of corticosterone induce PDE4 which caused depression and anxiety-like behaviors in mice. The procedure involved using 100 μM of corticosterone which led to the induction of subtypes of PDE4 in mice: PDE2A, PDE3B, PDE4A, PDE4D, PDE10, and PDE11.

The mechanism of action of PDE4 is via the reduction of cyclic adenosine monophosphate. Adenosine monophosphate is a messenger molecule whose role is to signal physiological changes such as cell division, change or death which leads to physical changes in the brain. By inhibiting the expression of PDE4, resveratrol displays neuroprotective effects against corticosterone.

Related research

Researchers from Xinxiang Medical University grouped rats with induced depression into groups: control, low dose, medium dose, and high dose group. The control group received saline whereas the other groups received 10, 20 and 30mg/kg of resveratrol respectively. The treatment continued for 21 days. Results revealed an increase in dopamine and serotonin and neuropeptide Y expression which play an antagonist role in depression.

Hippocampal Plasticity Enhancer

One of the main goals of modern neuroscience is finding ways of restoring hippocampal plasticity in neurological and psychiatric disorders. Neural plasticity is the ability of the brain to respond to changes in the environment.

The hippocampus continuously generates new neurons throughout human life through a process called adult hippocampal neurogenesis (AHN). Resveratrol which has been reported to have antioxidant and antitumor properties has recently spurred scientists’ interests with its potential role as an inducer of neural plasticity.

Stress has been widely accepted as a risk factor for depression. Animal models have suggested this by exposing rats to unpredictable chronic mild stress (UCMS) which led to the display of depressive-related behaviors.

The behavioral changes in response to stress are often followed by hippocampal changes including attenuated AHN and brain-derived neurotrophic factor (BDNF). Intraperitoneal injections of resveratrol in mice not only induced similar behavioral effects as antidepressant medication but also restored levels of BDNF.

Overall, research findings reveal that resveratrol can improve mood and cognition and enhance AHN and neural plasticity. However, there is still some controversy around the role of resveratrol in hippocampal neuroplasticity that gives the contradictory results shown by some studies.

These studies report the opposite effect of resveratrol namely inhibiting AHN. Thus, further research is needed before resveratrol can be considered an established modulator of hippocampal plasticity and can be used in the prevention and treatment of neuropsychiatric conditions.

Final remarks

Even though research has advanced remarkably in recent years in the field of neuroscience and more particularly in the treatment and prevention of neuropsychiatric conditions there is still a long way to go to find novel pharmacological methods and validate the efficacy and application of these methods. Preliminary research has demonstrated that resveratrol has the potential to ameliorate chronic stress-induced depression and anxiety behaviors in animal models via the inhibition of PDE4 or potentiation of hippocampal plasticity.

Certain factors such as dose, condition, the form of administration and treatment duration still need to be validated before large scale clinical trials can be conducted and resveratrol can be put into practice and used as part of the treatment of the clinical population. Nevertheless, the recent findings lay the groundwork for the use of resveratrol in novel antidepressant medication.

References

Gu, Z. et al. (2019). The therapeutic effect of resveratrol on mice with depression. https://www.ncbi.nlm.nih.gov/pubmed/30936978

Zhu, X. et al. (2019). The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition. https://www.sciencedirect.com/science/article/pii/S002839081930139X

Dias, G. et al (2016). Resveratrol: A Potential Hippocampal Plasticity Enhancer. https://www.hindawi.com/journals/omcl/2016/9651236/abs/

Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines 2018, 6, 91. 10.3390/biomedicines6030091