Scientists have identified two grape-derived compounds that can effectively help to treat and protect against stress-induced depression in mice, and which could represent promising new candidates for treating depression in humans. The compounds, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc), trigger epigenetic changes in genes that affect inflammation and synaptic plasticity, mechanisms that aren’t addressed by current antidepressants.

“Our approach to use a combination treatment of DHCA and Mal-gluc to simultaneously inhibit peripheral inflammation and modulate synaptic plasticity in the brain works synergistically to optimize resilience against chronic stress-induced depression-like phenotypes,” says lead researcher Giulio Maria Pasinetti, Ph.D., Saunders Professor of Neurology at the Center for Integrative Molecular Neuroresilience, Icahn School of Medicine at Mount Sinai. “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.”

Professor Pasinetti and colleagues report their findings in Nature Communications, in a paper entitled “Epigenetic Modulation of Inflammation and Synaptic Plasticity Promotes Resilience against Stress in Mice.”

Major depressive disorder (MDD) is linked with brain and immune system abnormalities, the researchers explain. Studies in animals with chronic stress have demonstrated that epigenetic and inflammatory mechanisms play “important roles in mediating resilience and susceptibility to depression.” Previous studies have linked chronic stress in both humans and rodents, with changes in the level of a gene known as Rac1 in the nucleus accumbens (NAc region) of the brain, and associated downregulation of the Rac1 gene with changes to chromatin. “These studies suggest Rac1-mediated synaptic remodeling in the NAc, and associated epigenetic changes, can be potential targets for depressive disorders,” the researchers note.

Other research has separately implicated increased expression of the proinflammatory cytokine interleukin 6 (IL-6) in depressive disorders, which also indicates that “modulations of IL-6 and associated immune signaling pathways may provide novel therapeutic strategies to prevent and/or treat depression.”

Despite the key roles of inflammation and brain synaptic remodeling in the pathogenesis of depression, however, “currently available antidepressants do not specifically address MDD-associated inflammation and synaptic maladaptation,” Instead, they generally target systems that regulate serotonin, dopamine, and other related neurotransmitters.

Previous work has found that grape-derived polyphenols can have a positive impact on some aspects of depression, but how they worked hasn’t been understood. The Icahn School of Medicine team has now demonstrated that a bioactive dietary polyphenol preparation (BDPP)—composed of a specific Concord grape juice, grape seed extract, and trans-resveratrol—can protect mice against developing stress-mediated depression. The team has also used high-throughput screening to identify two specific compounds that work together to provide resilience against stress-induced depression in established mouse models.

The two compounds, DHCA and Mal-gluc, work by modulating inflammation and synaptic plasticity, respectively. DHCA treatment was found to trigger epigenetic changes to the noncoding sequence of IL-6, which resulted in reduced production of the cytokine by T cells and macrophages. Mal-gluc was shown to modulate histone acetylation of the Rac1 gene, so that transcription activators could access the DNA and increase transcription in the brain, which influences the expression of genes responsible for synaptic plasticity.

Testing the two compounds as combination prophylactic therapy in a mouse model that recapitulates stress-induced depression in humans showed that treated animals were less likely to demonstrate the depressive-like behaviors. In a second set of in vivo experiments in mice, the researchers showed that DHCA/Mal-gluc therapy was about as effective as an existing antidepressant, imipramine, at treating a social avoidance-type behavior. Further evaluation showed tht DHCA/Mal-gluc treatment led to increased Rac1 expression in the NAc region of the brain.

In a third set of studies, the researchers found that DHCA/Mal-gluc therapy effectively reduced depressive-like behaviors in a mouse model of increased systemic inflammation induced by transplanting bone marrow cells from stress-susceptible mice. “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,” says Jun Wang, Ph.D., associate professor of the department of neurology, who is first author of the Nature Communications paper.

“Our evidence suggests that both DHCA and Mal-gluc contribute to resilience against the development of depression-like phenotypes by modulating, respectively, pathological mechanisms relating to IL-6 and Rac1,” the authors conclude. Encouragingly, the combined therapy was just as effective in male and female animals. “We found that DHAC/Mal-gluc is effective in alleviating non-social stress induced depression-like behavior including self-neglect and anxiety in both male and female mice, further confirming the efficacy of the treatment,” they wrote.

The researchers say their findings support the development of DHCA/Mal-gluc as a novel therapeutic approach against treatment-resistant MDD, “particularly among the majority of patients who are characterized by high plasma levels of IL-6,” they write. And because the new compounds do not interact with the monoaminergic systems that are targeted by classical antidepressants, it’s possible that they could be used in combination with currently available antidepressants to target multiple disease mechanisms.

“Given the safety and drug-like profile, and the lack of direct interaction with key molecular components of the monoaminergic system, and the demonstrated efficacy in both males and females in [the] experimental model, DHCA/Mal-gluc can immediately translate into human clinical studies for the treatment of stress disorders and depression either alone or in combination with currently available antidepressants.”


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