A new study has revealed that the plant compound resveratrol, which is found in red wine, displays anti-stress effects by blocking the expression of an enzyme related to the control of stress in the brain.

Protection Against Extreme Stress

Resveratrol, which has been linked to a number of health benefits, is a compound found in the skin and seeds of grapes and berries. While research has identified resveratrol to have antidepressant effects, the compound’s relationship to phosphodiesterase 4 (PDE4), an enzyme influenced by the stress hormone corticosterone, was unknown. Corticosterone regulates the body’s response to stress. Too much stress, however, can lead to excessive amounts of the hormone circulating in the brain and, ultimately, the development of depression or other mental disorders.

These unknown physiological relationships make drug therapy complex. Current antidepressants instead focus on serotonin or noradrenaline function in the brain, but only one-third of patients with depression enter full remission in response to these medications.

Why PDE4 and cAMP?

Important in many biological processes, cAMP is a second messenger. These molecules respond to signals outside the cell, such as hormones, and pass the message on to the relevant regions within the cell. The authors of the current study explain:

“Considering that cAMP is a primary regulator for intracellular communication in the brain, it is an attractive target for therapeutic intervention in mental disorders.”

Earlier studies have shown that resveratrol increases levels of cAMP in a number of cell types. PDE4 is a family of enzymes that break down cAMP, helping regulate the levels of this molecule within cells. Higher levels of PDE4 lead to an increased breakdown of cAMP. Some earlier studies have hinted at the role of PDE4 in depression and anxiety.

The stress model of depression

Experts still do not fully understand what causes depression and why it affects some people but not others. One theory is called the glucocorticoid hypothesis. The body releases glucocorticoids, which include cortisol, when a person feels stressed. In the short term, these hormones help ready the body for an impending crisis. However, if the stress lasts for a longer time, glucocorticoids can begin to cause harm. In this way, some scientists believe that chronic stress damages neurons in the hippocampus, which are particularly sensitive. This damage then paves the way for anxiety and depression.

The authors of the current study were particularly interested in understanding whether resveratrol could reverse the damaging effects of stress and how this might work.

In their study, they found that increased levels of corticosterone (the rodent equivalent of cortisol) produced cell lesions in the brain and increased levels of PDE4D — a member of the PDE4 family that scientists believe to be particularly important in cognition and depression. They also showed that treatment with resveratrol reversed the increase in PDE4D and reduced the number of cell lesions. Resveratrol also prevented the decrease in cAMP. In engineered mice that could not produce PDE4D, resveratrol boosted cAMP’s protective effects even further than in mice with functioning PDE4D.

The authors write that “[t]hese findings provide evidence that the antidepressant- and anxiolytic-like effects of resveratrol are predominantly mediated by PDE4D inhibition.”

Resveratrol displayed neuroprotective effects against corticosterone by inhibiting the expression of PDE4. The research lays the groundwork for the use of the compound in novel antidepressants. According to the researchers, although red wine contains resveratrol, consumption of alcohol has various health risks, including addiction.

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