RESUMO
BACKGROUND: Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. METHODS: Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 -/- ) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 -/- mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. RESULTS: DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 -/- mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. CONCLUSIONS: DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.
Assuntos
Fumarato de Dimetilo/uso terapêutico , Imunossupressores/uso terapêutico , Inflamação/complicações , Transtornos da Memória , Microglia/efeitos dos fármacos , Animais , Receptor 1 de Quimiocina CX3C/deficiência , Receptor 1 de Quimiocina CX3C/genética , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Inflamação/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacosRESUMO
Trm4p from Saccharomyces cerevisiae and its mammalian orthologue Nsun2 fabricate 5-methylcytosine (m(5)C) in RNA molecules utilizing a dual-cysteine catalytic mechanism. These enzymes are now shown to form covalent complexes with previously methylated RNA. Enzyme linkage to methylated RNA requires S-adenosylhomocysteine (AdoHcy), and the removal of this metabolite results in the disassembly of preexisting complexes. The fraction of Trm4p linked to modified RNA is influenced by the AdoHcy concentration and by the pH of the solution, with maximal formation of Trm4p-RNA complexes observed in the pH range of 5.5-6.5. Four active-site residues critical for Trm4p-mediated tRNA methylation are also required for the formation of the denaturant-resistant complexes with m(5)C-containing RNA. On the basis of these findings, it is proposed that formation of a covalent complex between dual-cysteine RNA:m(5)C methyltransferases and methylated RNA provides a unique means by which metabolic factors can influence RNA. By controlling the degree of formation of the enzyme-RNA covalent complex, AdoHcy and pH are likely to influence the extent of m(5)C formation and the rate of release of methylated RNA from RNA:m(5)C methyltransferases. Metabolite-induced covalent complexes could plausibly affect the processing and function of m(5)C-containing RNAs.
