malvidin-3-glucoside and 3-4-dihydroxyphenylpropionic-acid

Neurexins (NRXNs) are cell-adhesion molecules important in the formation and remodeling of neural circuits. It has been shown that aversive environmental stimuli can affect the expression pattern of Neurexin genes (Nrxns) impacting the regulation of synaptic strength. Accumulated evidence suggests that, after chronic exposure to psychological stress, the triggered changes in gene expression and splicing patterns of Nrxns may be involved in aversive conditioning. Previously, we have demonstrated that a novel treatment using dietary phytochemicals can modulate the response to chronic variable stress (CVS) in mice. Here, we aimed to further investigate the long-term plasticity changes after CVS by focusing on the regulation of NRXNs at synapses. We found that CVS differentially triggers the region-specific gene expression of Nrxns in mice Nucleus Accumbens (NAc) and Hippocampus (HIPP). The prophylactic treatment with the combination of two phytochemicals dihydrocaffeic acid (DHCA) and Malvidin-3-O-glucoside (Mal-gluc) differentially modulated the stress-induced effects on Nrxn1 and 3 mRNA expression in these brain areas and promoted the alternative splicing of Nrxn3 in HIPP. Overall, our data supports the prophylactic effect of dietary phytochemicals in the restoration of stress-induced plasticity changes in mouse brain. By intervening in activity-dependent plasticity at synapses, these compounds may attenuate the effects of chronic aversive conditioning. We propose that an early therapeutic intervention may help with disorders of negative affect, such as depression or post-traumatic stress disorder. Our future studies will address how DHCA/Mal-gluc might serve as a potential complement for current therapies in depression and other mood disorders.

Topics: Alternative Splicing; Animals; Anthocyanins; Behavior, Animal; Brain; Caffeic Acids; Calcium-Binding Proteins; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Female; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Neuronal Plasticity; Neurons; Phytochemicals; Stress, Psychological; Synapses

Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. 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. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.

Topics: Animals; Anthocyanins; Caffeic Acids; CpG Islands; Depression; Drug Evaluation, Preclinical; Epigenesis, Genetic; Glucosides; Inflammation; Interleukin-6; Leukocyte Common Antigens; Male; Mice, Inbred C57BL; Neuronal Plasticity; Neuropeptides; Polyphenols; rac1 GTP-Binding Protein; Social Behavior; Stress, Psychological

Stress is a known contributor to various forms of disease in humans and animals, although mechanisms are still unknown. In animals, psychosocial stress-induced depression/anxiety phenotypes are coincidental with increased inflammation in both brain and blood. The authors recently showed that a novel treatment with a select bioactive polyphenol preparation promotes resilience to stress-mediated depression/anxiety phenotypes mice. Moreover, selective bioactive phenolic compounds within the polyphenol preparation are identified that are effective in mitigating the behavioral effects of bone marrow transplantation from stressed mice.. Here, an animal model of adult stress and bone marrow transplantation is used to identify an epigenetic signature of repeated social defeat stress (RSDS) that is passed through bone marrow hematopoietic progenitor cells to naïve mice, revealing the maintenance of epigenetic memory following stress both centrally and peripherally. Further, polyphenols are administered to naïve and stress-susceptible mice, demonstrating that polyphenol treatment in mice from both susceptible and naïve donors alters global DNA methylation in the central nervous system and periphery and likewise has an effect on human blood cells after immune challenge.. Findings highlight the enduring molecular memory of stress and the possible mechanism by which select bioactive polyphenols may promote resiliency to stress. Polyphenols may be an efficacious alternative to traditional pharmacological treatments in psychiatry.

Topics: Adult; Animals; Anthocyanins; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Behavior, Animal; Bone Marrow Transplantation; Brain; Caffeic Acids; Cells, Cultured; Depression; Dietary Supplements; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Glucosides; Humans; Immunity, Cellular; Leukocytes, Mononuclear; Male; Mice, Inbred C57BL; Neurons; Social Behavior; Stress, Psychological