A new study unravels the mechanism by which compounds found in grapes improve resilience to stress in mice and attenuate the brain changes linked with depression.

According to the Anxiety and Depression Association of America, major depressive disorder, or clinical depression, is now "the leading cause of disability" among people between age 15 and 44 years in the United States.

Every year, more than 16 million US adults are affected. This is the equivalent of around 6.7% of the country's adult population.

Conventional drug treatments for depression are not particularly effective. In fact, the authors of the new study say that less than 50% of those diagnosed with depression experience temporary remission of the illness.

The need for alternative treatments is therefore dire. This is why the scientists—led by Giulio Maria Pasinetti, a professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City, NY—set out to investigate an alternative route for treating depression.

This route involves the potentially beneficial effect of compounds derived from grapes. Previous research has shown that so-called grape polyphenols have some efficacy in managing major depressive disorder, but the precise mechanisms behind this were unclear.

The new study by Professor Pasinetti and his team explains this mechanism. The researchers tested the effect of a mix of three polyphenols derived from grapes in mice and published their results in the journal Nature Communications.

BDPP, inflammation, and synaptic plasticity

The mixture the researchers used is called a "bioactive dietary polyphenol preparation" (BDPP), and it is made of Concord grape juice, an extract from grape seeds, and trans-resveratrol.

In addition to testing BDPP, the researchers also tested the effect of two new phytochemicals that are derived from metabolizing BDPP.

Professsor Pasinetti and team administered BDPP to a group of mice that had been chronically stressed. They found that the preparation improved the mice's resilience against stress-induced depression.

Specifically, the way that BDPP did this was by modulating the plasticity of the brain's synapses, or the connections between neurons, and by modulating inflammation.

Previous experiments in which mice were chronically stressed had shown that "epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression."

In the study, the team demonstrates how one of the two new phytochemicals reduces levels of a pro-inflammatory substance and how the other intervenes epigenetically to raise the expression of genes, which, in turn, promotes synaptic plasticity.

"Our research shows that combination treatment with the two compounds can promote resilience against stress-mediated depression-like phenotypes by modulating systemic inflammatory responses and brain synaptic plasticity in a mouse model of depression."

First study author Jun Wang, PhD

The researchers note that this discovery brings us closer to a treatment for the alternative, often ignored mechanisms of depression—such as inflammation and the malfunctioning of synapses.

"Our approach to use a combination treatment of DHCA and Mal-gluc [the two phytochemicals] to simultaneously inhibit peripheral inflammation and modulate synaptic plasticity in the brain," says Professor Pasinetti, "works synergistically to optimize resilience against chronic stress-induced depression-like phenotypes."

He continues, "The discovery of these new, natural grape-derived polyphenol compounds targeting cellular and molecular pathways associated with inflammation may provide an effective way to treat a subset of people with depression and anxiety, a condition that affects so many people."