A nice, relaxing glass of Bordeaux or Cabernet might easily seem like the perfect treatment for an anxious or slightly depressed state. Though, the alcohol might lead one down a slippery path rather quickly. Instead, investigators at the University of Buffalo (UB) and Xuzhou Medical University in China have decided to focus their attention on the widely studied plant compound—found in considerably higher levels in red wine than most other plants—called resveratrol. This phenolic compound has been studied for several decades, in connection with reduced incidence of cardiovascular disease and for the treatment of cancer, with mixed results. Yet now, researchers found new evidence of resveratrol displaying anti-stress effects by blocking the expression of an enzyme related to the control of stress in the brain.

Findings from the new study—published recently in Neuropharmacology through an article titled “The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition”—shed light onto how resveratrol impacts neurological processes. According to the Anxiety and Depression Association of America, depression and anxiety disorders affect 16 and 40 million people respectively in the United States.

“Resveratrol may be an effective alternative to drugs for treating patients suffering from depression and anxiety disorders,” explained co-senior study investigator Ying Xu, MD, PhD, research associate professor in the UB School of Pharmacy and Pharmaceutical Sciences.

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.

“We found that 100 μM corticosterone induced PDE2A, PDE3B, PDE4A, PDE4D, PDE10, and PDE11 expression in HT-22 cells, which results in significant cell lesion. However, treatment with resveratrol increased cell viability in a dose- and time-dependent manner,” the authors found. “These effects seem related to the inhibition of PDE4D, as evidenced by resveratrol dose-dependently decreasing PDE4D expression. In addition, the PKA inhibitor H89 reversed resveratrol’s effects on cell viability. Resveratrol prevented corticosterone-induced reduction in cAMP, pVASP(s157), pCREB, and BDNF levels, indicating that cAMP signaling is involved in resveratrol-induced neuroprotective effects. Not to mention, PDE4D knockdown by PDE4D siRNA potentiated the effect of low dose of resveratrol on cAMP, pVASP, pCREB, and BDNF expression, while PDE4D overexpression reversed the effect of high dose of resveratrol on the expression of the above proteins.”

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, noted Xu.

In the current study, which was done in mice, the researchers revealed that PDE4, induced by excessive amounts of corticosterone, causes depression- and anxiety-like behavior. The enzyme lowers cyclic adenosine monophosphate—a second messenger molecule that signals physiological changes such as cell division, change, migration, and death—in the body, leading to physical alterations in the brain.

Interestingly, 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. Although red wine contains resveratrol, consumption of alcohol carries various health risks, including addiction, the authors advised.

“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 behavior,” the authors concluded.

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