RESUMO
Rationale: The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1ß in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1ß secretion in vitro, the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Methods: Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. Results: We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of Il-1ß gene expression in this experimental model. Conclusion: Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients.
Assuntos
Gota/tratamento farmacológico , Imiquimode/farmacologia , Inflamação/induzido quimicamente , Interleucina-1beta/efeitos dos fármacos , Ácido Úrico/efeitos adversos , Doença Aguda , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Administração Tópica , Animais , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Citocinas/metabolismo , Modelos Animais de Doenças , Gota/metabolismo , Gota/patologia , Imiquimode/administração & dosagem , Imiquimode/uso terapêutico , Inflamação/diagnóstico , Inflamação/imunologia , Injeções Subcutâneas , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Knockout , Ácido Úrico/administração & dosagemRESUMO
Caffeine is not considered addictive, and in animals it does not trigger metabolic increases or dopamine release in brain areas involved in reinforcement and reward. Our objective was to measure caffeine effects on cerebral perfusion in humans using single photon emission computed tomography with a specific focus on areas of reinforcement and reward. Two groups of nonsmoking subjects were studied, one with a low (8 subjects) and one with a high (6 subjects) daily coffee consumption. The subjects ingested 3 mg/kg caffeine or placebo in a raspberry-tasting drink, and scans were performed 45 min after ingestion. A control group of 12 healthy volunteers receiving no drink was also studied. Caffeine consumption led to a generalized, statistically nonsignificant perfusion decrease of 6% to 8%, comparable in low and high consumers. Compared with controls, low consumers displayed neuronal activation bilaterally in inferior frontal gyrus-anterior insular cortex and uncus, left internal parietal cortex, right lingual gyrus, and cerebellum. In high consumers, brain activation occurred bilaterally only in hypothalamus. Thus, on a background of widespread low-amplitude perfusion decrease, caffeine activates a few regions mainly involved in the control of vigilance, anxiety, and cardiovascular regulation, but does not affect areas involved in reinforcing and reward.