RESUMO
BACKGROUND: According to the World Health Organization, as of 2014 9% of the world's adult population is affected by diabetes. Uncontrolled diabetes is a pro-inflammatory process that increases generation of reactive oxygen species (ROS). METHODS: The production of ROS leads to a chronic increase in oxidative stress which results in an increased susceptibility to infections. Individuals with type 2 diabetes mellitus (T2DM) are highly susceptible to Mycobacterium tuberculosis (M. tb) infection. Previous research has demonstrated that glutathione (GSH) plays an important role in the control of M. tb infection. Recent studies have demonstrated that phagocytosis of M.tb is diminished in patients with T2DM. Phagocytosis in macrophages is thought to be mediated in part by complement protein 3b (C3b)-complement protein receptor 3b (C3R) interactions. Since C3b production is not diminished in patients with T2DM we propose that C3R production is reduced and is the cause for impaired macrophage phagocytosis as well as IL-12 and IFN-γ signaling. CONCLUSION: This study utilizes a quantitative PCR (qPCR), demonstrating decreased transcription of C3R mRNA in patients with T2DM as compared to non-diabetics.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Antígeno de Macrófago 1/biossíntese , RNA Mensageiro/biossíntese , Adulto , Idoso , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Regulação da Expressão Gênica , Humanos , Antígeno de Macrófago 1/genética , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Mycobacterium tuberculosis/metabolismo , RNA Mensageiro/genética , Tuberculose/epidemiologia , Tuberculose/genética , Tuberculose/metabolismoRESUMO
Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies.
Assuntos
Modelos Animais de Doenças , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Nitroglicerina , Propranolol/administração & dosagem , Sumatriptana/administração & dosagem , Ácido Valproico/administração & dosagem , Doença Aguda , Amilorida/administração & dosagem , Animais , Anticonvulsivantes/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Transtornos de Enxaqueca/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Especificidade da Espécie , Resultado do Tratamento , Vasodilatadores/administração & dosagemRESUMO
Chronic migraine is a disabling condition that affects hundreds of millions of individuals worldwide. The development of novel migraine treatments has been slow, in part as a result of a lack of predicative animal models. We have developed a new model of chronic migraine involving the use of nitroglycerin (NTG), a known migraine trigger in humans. Chronic intermittent administration of NTG to mice resulted in acute mechanical hyperalgesia with each exposure as well as a progressive and sustained basal hyperalgesia. This chronic basal hyperalgesia occurred in a dose-dependent fashion and persisted for days after cessation of NTG administration. NTG-evoked hyperalgesia was exacerbated by the phosphodiesterase 5 inhibitor sildenafil, also a human migraine trigger, consistent with nitric oxide as a primary mediator of this hyperalgesia. The acute but not the chronic basal hyperalgesia was significantly reduced by the acute migraine therapy sumatriptan, whereas both the acute and chronic hyperalgesia was significantly attenuated by the migraine preventive therapy topiramate. Chronic NTG-induced hyperalgesia is a mouse model that may be useful for the study of mechanisms underlying progression of migraine from an episodic to a chronic disorder, and for the identification and characterization of novel acute and preventive migraine therapies.
