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
Prion infections induce severe disruption of the central nervous system with neuronal vacuolation and extensive glial reactions, and invariably lead to death of affected individuals. The molecular underpinnings of these events are not well understood. To better define the molecular consequences of prion infections, we analyzed the transcriptional response to persistent prion infection in a panel of three murine neural cell lines in vitro. Colony spot immunochemistry assays indicated that 65-100% of cells were infected in each line. Only the Nav1 gene was marginally modulated in one cell line, whereas transcripts previously reported to be derailed in prion-infected cells were not confirmed in the present study. We attribute these discrepancies to the experimental stringency of the current study, which was performed under conditions designed to minimize potential genetic drifts. These findings are at striking variance with gene expression studies performed on whole brains upon prion infections in vivo, suggesting that many of the latter changes represent secondary reactions to infection. We conclude that, surprisingly, there are no universal transcriptional changes induced by prion infection of neural cells in vitro.