RESUMEN
Cationic amphiphiles derived from trehalose have been synthesized; trehalose analogues substituted with n-pentyl or n-hexyl ethers exhibited membrane disrupting activities against clinically important Gram positive and Gram negative bacteria and fungi. Our results demonstrate that trehalose is a useful disaccharide scaffold for the development of broad-spectrum antimicrobial and antifungal agents.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Hongos/efectos de los fármacos , Trehalosa/análogos & derivados , Trehalosa/farmacología , Antiinfecciosos/síntesis química , Bacterias/citología , Infecciones Bacterianas/tratamiento farmacológico , Hongos/citología , Bacterias Gramnegativas/citología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/citología , Bacterias Grampositivas/efectos de los fármacos , Humanos , Modelos Moleculares , Micosis/tratamiento farmacológico , Trehalosa/síntesis químicaRESUMEN
OBJECTIVES: Minocycline is a tetracycline antibiotic increasingly recognized in psychiatry for its pleiotropic anti-inflammatory and neuroprotective potential. While underlying mechanisms are still incompletely understood, several lines of evidence suggest a relevant functional overlap with retinoic acid (RA), a highly potent small molecule exhibiting a great variety of anti-inflammatory and neuroprotective properties in the adult central nervous system (CNS). RA homeostasis in the adult CNS is tightly controlled through local RA synthesis and cytochrome P450 (CYP450)-mediated inactivation of RA. Here, we hypothesized that minocycline may directly affect RA homeostasis in the CNS via altering local RA degradation. METHODS: We used in vitro RA metabolism assays with metabolically competent synaptosomal preparations from murine brain and human SH-SY5Y neuronal cells as well as viable human SH-SY5Y neuroblastoma cell cultures. RESULTS: We revealed that minocycline potently blocks RA degradation as measured by reversed-phase high-performance liquid chromatography and in a viable RA reporter cell line, even at low micromolar levels of minocycline. CONCLUSIONS: Our findings provide evidence for enhanced RA signalling to be involved in minocycline's pleiotropic mode of action in the CNS. This novel mode of action of minocycline may help in developing more specific and effective strategies in the treatment of neuroinflammatory or neurodegenerative disorders.
Asunto(s)
Encéfalo/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Minociclina/farmacología , Neuronas/efectos de los fármacos , Tretinoina/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Humanos , Masculino , Neuroblastoma/metabolismo , Ratas , Ratas Wistar , Análisis de RegresiónRESUMEN
The effect of aprotinin on metabolic changes in blood of 23 patients undergoing Y-graft aortofemoral bypass operation was studied before clamping and after declamping. The right femoral artery was clamped for 122 +/- 15 (-aprotinin) and 115 +/- 10 min (aprotinin group), the left femoral artery 129 +/- 27 (-aprotinin) and 159 +/- 25 min (aprotinin group), respectively. Aprotinin caused a significant decrease of blood lactate, pyruvate, citrate and oxoglutarate levels compared with untreated controls, whereas acetoacetate and beta-hydroxybutyrate concentrations were significantly increased. It is hypothesized that blood lactate and pyruvate levels are lowered due to increased pyruvate oxidation. Limitation of citrate synthesis due to lack of oxaloacetate might explain subsequent formation of ketone bodies.