# Development of dihydrocaffeic acid and malvidin- 3 - glucoside for the treatment of depression and anxiety disorders

> **NIH VA I01** · JAMES J PETERS VA  MEDICAL CENTER · 2020 · —

## Abstract

Depression, anxiety, and other stress-related disorders are widespread psychological conditions with broad
health implications, including negative impacts on cardiovascular and metabolic functions and on mental
health, including memory dysfunction. The prevalence of depression is even higher in veterans. It was
estimated that approximately 30% of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF)
veterans are affected by depression. Current available treatments for depression mainly target the serotonergic
and noradrenergic system and only produce temporary remission in less than 50% of patients with wide range
of “adverse” events. There is an urgent need for new therapeutics to treat specific underlying disease
mechanisms that are not addressed by standard antidepressants.
Stress-mediated synaptic maladaptation of nucleus accumbens (NAc) and induction of inflammatory cytokines
in the periphery contribute to depression-like behaviors both in humans and in experimental models. Both
peripheral inflammation and synaptic plasticity maladaptation have emerged as newly hypothesized clinical
intervention targets for depression. We recently identified two phytochemicals, namely dihydrocaffeic acid
(DHCA) and malvidin-3-O-glucoside (Mal-gluc) that are effective in preventing and treating depression in
multiple experimental models of depression and in both males and females. We found DHCA reduces pro-
inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences
introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory
sequences of the Rac1 gene. By simultaneously targeting peripheral inflammation and synaptic maladaptation,
DHCA and Mal-gluc synergistically promote resilience against stress-induced depression phenotypes including
social isolation, anhedonia, self-neglect and anxiety in animal models of depression. In vitro toxicity and drug-
like properties studies have shown that both compounds are deemed to be safe and have acceptable drug-like
properties. In vivo safety studies also showed that 2-week treatment with DHCA with dose 10 times higher than
the efficacious dose, and Mal-gluc with dose 100 times higher than the efficacious dose, did not lead to any
adverse toxicity in mice. Based on these evidence, the overall goal of the Merit application is to conduct a
thorough pharmacology and toxicology studies to gather sufficient pharmacological and safety information of
the two lead compounds. Specifically, we propose to conduct oral bioavailability studies, pharmacokinetics and
toxicokinetics studies on single oral dose, 4-week subchronic and 6-month chronic treatment of the two
compounds either provided individually or in combination. The information gathered from the proposed studies
will provide critical data required by the FDA for moving forward to translational application of the two
compounds in human Phase I clinical studies.
O...

## Key facts

- **NIH application ID:** 9775769
- **Project number:** 1I01BX004743-01
- **Recipient organization:** JAMES J PETERS VA  MEDICAL CENTER
- **Principal Investigator:** Jun Wang
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9775769

## Citation

> US National Institutes of Health, RePORTER application 9775769, Development of dihydrocaffeic acid and malvidin- 3 - glucoside for the treatment of depression and anxiety disorders (1I01BX004743-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9775769. Licensed CC0.

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