RESUMEN
Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid ß accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/metabolismo , Glucosamina/farmacología , Hipoxia/metabolismo , Pez Cebra/metabolismo , Proteínas tau/metabolismo , Animales , Ansiedad/metabolismo , Encéfalo/metabolismo , Estudios de Casos y Controles , Disfunción Cognitiva/etiología , Encefalitis/metabolismo , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Glucosamina/metabolismo , Glucosamina/uso terapéutico , Glucosa/metabolismo , Hipoxia/complicaciones , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/prevención & control , Discapacidades para el Aprendizaje/metabolismo , Masculino , Trastornos de la Memoria/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Proteínas de Pez Cebra/metabolismo , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
Enterolacaciamine (1), a new potential O-GlcNAcase activator, along with three known triterpenoid saponins, concinnoside B (2), concinnoside D (3), and julibroside A3 (4) was isolated from the leaves of Enterolobium cyclocarpum. Their structures were elucidated by chemical and spectroscopic methods (UV, MS, 1D and 2D NMR). Their effects on O-GlcNAcase activity were evaluated using O-GlcNAcase enzymatic assay. The results showed that compound 1 could obviously enhance the activity of O-GlcNAcase.