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
Disease-modifying therapies are being developed for Alzheimer's disease (AD). These are expected to slow the clinical progression of the disease or delay its onset. Cerebral accumulation of amyloid beta (A beta) peptides is an early and perhaps necessary event for establishing AD pathology. Consequently therapies aimed at attenuating brain amyloidosis are expected to be disease modifying. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of A beta production and accumulation, it is now believed that cholesterol-lowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. These observations require both preclinical and clinical validation. The former involves testing statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes. The latter requires prospective, randomized, placebo controlled trials to evaluate the effect of statin treatment on cognitive and AD biomarker outcomes. We have initiated a study aimed at determining the effects of atorvastatin (Lipitor), a statin with the largest US market share, on brain A beta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis. Our results indicate that Lipitor treatment markedly attenuates A beta deposition in this animal model.