RESUMO
Given their important role in neuronal function, there has been an increasing focus on altered lipid levels in brain disorders. The effect of a high-fat (HF) diet on the lipid profiles of the cortex, hippocampus, hypothalamus, and olfactory bulb of the mouse brain was investigated using nanoflow ultrahigh pressure liquid chromatography-electrospray ionization-tandem mass spectrometry in the current study. For 8â¯weeks, two groups of 5-week-old mice were fed either an HF or normal diet (6 mice from each group analyzed as the F and N groups, respectively). The remaining mice in both groups then received a 4-week normal diet. Each group was then subdivided into two groups for another 4-week HF or normal diet. Quantitative analysis of 270 of the 359 lipids identified from brain tissue revealed that an HF diet significantly affected the brain lipidome in all brain regions that were analyzed. The HF diet significantly increased diacylglycerols, which play a role in insulin resistance in all regions that were analyzed. Although the HF diet increased most lipid species, the majority of phosphatidylserine species were decreased, while lysophosphatidylserine species, with the same acyl chain, were substantially increased. This result can be attributed to increased oxidative stress due to the HF diet. Further, weight-cycling (yo-yo effect) was found more critical for the perturbation of brain lipid profiles than weight gain without a preliminary experience of an HF diet. The present study reveals systematic alterations in brain lipid levels upon HF diet analyzed either by lipid class and molecular levels.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Metaboloma , Bulbo Olfatório/efeitos dos fármacos , Animais , Química Encefálica , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão , Diglicerídeos/agonistas , Diglicerídeos/metabolismo , Hipocampo/metabolismo , Hipotálamo/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bulbo Olfatório/metabolismo , Estresse Oxidativo , Fosfatidilserinas/antagonistas & inibidores , Fosfatidilserinas/metabolismo , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistasRESUMO
BACKGROUND: Increased vascular leakage leading to hypovolaemia and tissue oedema is common in severe sepsis. Hypovolaemia together with oedema formation may contribute to hypoxia and result in multiorgan failure and death. To improve treatment during sepsis, a potential therapeutic target may be to reduce the vascular leakage. Substances affecting the endothelial barrier are interesting in this respect, as it is suggested that increase in vascular leakage depends on reorganisation of the endothelial cells and breakdown of the endothelial barrier. The agonist of the bioactive lipid sphingosine-1-phosphate, FTY720, has been shown to modulate the integrity of the endothelium and reduce permeability both in vitro and in vivo. The aim of the present study was to determine if FTY720 could reduce the loss of plasma volume during experimental sepsis in rats. METHODS: Sepsis was induced by ligation and incision of the caecum in the rat. Plasma volume was determined before and 4.5 h after induction of sepsis by a dilution technique using (125) I-labelled albumin. RESULTS: FTY720 in a dose of 0.2 mg/kg reduced the loss of plasma during sepsis by approximately 30% compared with vehicle, without any adverse effects on haemodynamic and physiological parameters. The increase in hematocrit and haemoglobin concentration was also found to be higher in the vehicle group. CONCLUSION: FTY720 in a dose without haemodynamic side effects reduces loss of plasma volume during experimental sepsis most likely because of reduction in permeability and may therefore be beneficial in sepsis.
Assuntos
Lisofosfolipídeos/agonistas , Volume Plasmático/efeitos dos fármacos , Propilenoglicóis/uso terapêutico , Sepse/fisiopatologia , Esfingosina/análogos & derivados , Animais , Síndrome de Vazamento Capilar/tratamento farmacológico , Síndrome de Vazamento Capilar/etiologia , Permeabilidade Capilar/efeitos dos fármacos , Ceco/lesões , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Edema/etiologia , Edema/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Cloridrato de Fingolimode , Hematócrito , Hemodinâmica/efeitos dos fármacos , Hemoglobinas/análise , Perfuração Intestinal/complicações , Masculino , Propilenoglicóis/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sepse/sangue , Sepse/etiologia , Esfingosina/agonistas , Esfingosina/farmacologia , Esfingosina/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: We have previously shown that the sphingosine 1-phosphate (S1P)/S1P receptor-1 (S1P(1)R) axis contributes to the migration of transplanted neural progenitor cells (NPCs) toward areas of spinal cord injury. In the current study, we examined a strategy to increase endogenous NPC migration toward the injured central nervous system to modify S1PR. METHODS: S1P concentration in the ischemic brain was measured in a mouse thrombosis model of the middle cerebral artery. NPC migration in vitro was assessed by a Boyden chamber assay. Endogenous NPC migration toward the insult was evaluated after ventricular administration of the S1P(2)R antagonist JTE-013. RESULTS: The concentration of S1P in the brain was increased after ischemia and was maximal 14 days after the insult. The increase in S1P in the infarcted brain was primarily caused by accumulation of microglia at the insult. Mouse NPCs mainly expressed S1P(1)R and S1P(2)R as S1PRs, and S1P significantly induced the migration of NPCs in vitro through activation of S1P(1)R. However, an S1P(1)R agonist failed to have any synergistic effect on S1P-mediated NPC migration, whereas pharmacologic or genetic inhibition of S1P(2)R by JTE-013 or short hairpin RNA expression enhanced S1P-mediated NPC migration but did not affect proliferation and differentiation. Interestingly, administration of JTE-013 into a brain ventricle significantly enhanced endogenous NPC migration toward the area of ischemia. CONCLUSIONS: Our findings suggest that S1P is a chemoattractant for NPCs released from an infarcted area and regulation of S1P(2)R function further enhances the migration of NPCs toward a brain infarction.