RESUMO
The cystic fibrosis (CF) intestine is characterized by chronic inflammation. CF patients are instructed to ingest supplemental vitamin D on a daily basis thereby exposing their intestinal tract to pharmacological amounts of this vitamin. It has been shown that vitamin D exerts intestinal anti-inflammatory properties. We therefore postulate that vitamin D may be beneficial in the management of CF intestinal inflammation by attenuating cellular inflammatory responses. In this study, we investigated the anti-inflammatory effects of the oral form of vitamin D3 (cholecalciferol) and its metabolites, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, on cytokine-induced inflammatory responses in intestinal epithelial Caco-2/15 cells with intact expression of CF transmembrane conductance regulator (CFTR) and knockdown for CFTR. We show that 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 inhibited p38MAPK phosphorylation and that these effects were not mediated by changes in the expression of MAPK phosphatase-1 (MKP-1). However, 1,25-dihydroxyvitamin D3 exhibited superior anti-inflammatory effects as it furthermore reduced cytokine-induced NF-κB nuclear translocation and interleukin-8 mRNA stability and secretion. Intriguingly, the anti-inflammatory effects of vitamin D metabolites were only observed in CFTR knockdown cells, which may be explained by alterations in its catabolism associated with changes in CYP24A1 expression. These observations were supported in vivo whereby Cftr(-/-) mice fed large amounts of vitamin D3 for 2 mo led to a reduction in the number of eosinophils and apoptotic cells in the duodenal mucosa of females but not males. Altogether, these findings suggest that vitamin D exerts intestinal anti-inflammatory actions under specific circumstances and may thus prove beneficial in CF.
Assuntos
Anti-Inflamatórios/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Mucosa Intestinal/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Apoptose , Células CACO-2 , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Citocinas/genética , Citocinas/metabolismo , Fosfatase 1 de Especificidade Dupla/metabolismo , Feminino , Células HT29 , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
As a follow up of our previous structure-activity relationship and molecular modeling studies, we synthesized a novel series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as potential non-competitive AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these novel compounds showed high anticonvulsant potency.