RESUMO
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.
Assuntos
Antocianinas/farmacologia , Ácidos Cafeicos/farmacologia , Epigênese Genética , Glucosídeos/farmacologia , Inflamação/genética , Plasticidade Neuronal/genética , Estresse Psicológico/genética , Animais , Antocianinas/administração & dosagem , Ácidos Cafeicos/administração & dosagem , Ilhas de CpG/efeitos dos fármacos , Depressão/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Glucosídeos/administração & dosagem , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Antígenos Comuns de Leucócito/genética , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Polifenóis/farmacologia , Comportamento Social , Estresse Psicológico/tratamento farmacológico , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Mood disorders such as depression are among the most prevalent psychiatric disorders in the United States, but they are inadequately treated in a substantial proportion of patients. Accordingly, neuropsychiatric research has pivoted from investigation of monoaminergic mechanisms to exploration of novel mediators, including the role of inflammatory processes. Subsets of mood disorder patients exhibit immune-related abnormalities, including elevated levels of proinflammatory cytokines, monocytes, and neutrophils in the peripheral circulation; dysregulation of neuroglia and blood-brain barrier function; and disruption of gut microbiota. The field of psychoneuroimmunology is one of great therapeutic opportunity, yielding experimental therapeutics for mood disorders, such as peripheral cytokine targeting antibodies, microglia and astrocyte targeting therapies, and probiotic treatments for gut dysbiosis, and producing findings that identify therapeutic targets for future development.