Epigenetic Modulation Of Inflammation And Synaptic Plasticity By Polyphenolic Metabolites Promotes Resilience Against Stress In Mice
Abstract
Introduction: 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.
Material & Methods: 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.
Results: 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.
Conclusions:
This study suggests that polyphenolic metabolites capable of influencing peripheral inflammation and synaptic maladaptation may eventually be implemented as novel therapeutic interventions for promotion of mental health.
References
- Wang J, Gong B, Zhao W, Tang C, Varghese M, Nguyen T, Bi W, Bilski A, Begum S, Vempati P, Knable L, Ho L, Pasinetti GM. Epigenetic mechanisms linking diabetes and synaptic impairments. Diabetes 63(2):645-54 (2014).
- Herman F, Pasinetti GM. Principles of Inflammasome Priming and Inhibition: Implications for Psychiatric Disorders. Brain Behavior and Immunity DOI: 10.1016/j.bbi.2018.06.010 (2018).
- Herman F, Simkovic S, Pasinetti GM. The Neuroimmune Nexus of Depression and Dementia: Mechanisms and Targets. The British Journal of Pharmacology DOI: 10.1111/bph.14569 (2019).
DOI:
Issue: WAC 2022
Type: Article