RESUMEN
Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9beta,10xi-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca(2+) induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca(2+) concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.
Asunto(s)
Astrocitoma/metabolismo , Reacción de Prevención/efectos de los fármacos , Diterpenos/uso terapéutico , Discapacidades para el Aprendizaje/tratamiento farmacológico , Factor de Crecimiento Nervioso/metabolismo , Androsterona/análogos & derivados , Androsterona/farmacología , Androsterona/uso terapéutico , Animales , Astrocitoma/patología , Conducta Animal/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , AMP Cíclico/metabolismo , Diterpenos/química , Diterpenos/farmacología , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Fosfatos de Inositol/metabolismo , Discapacidades para el Aprendizaje/inducido químicamente , Masculino , Ratones , Neuritas/efectos de los fármacos , Células PC12 , Proto-Oncogenes Mas , Ratas , Escopolamina , Sales de Tetrazolio , TiazolesRESUMEN
Entomopathogenic fungi forming fruiting bodies have been employed as tonics and antitussives from ancient times. Paecilomyces tenuipes, which is also called Isaria japonica, is a very popular entomopathogenic fungus and is often considered a health food in northeast Asian countries such as China, Korea, and Japan. We cultivated the fruiting bodies of Paecilomyces tenuipes. Among the large-scale cultivations, fruiting body grown in barley grain contained two novel spirocyclic trichothecane derivatives, spirotenuipesine A (1) and B (2), and known trichothecane mycotoxins. Compounds 1 and 2 showed potent activity in neurotrophic factor biosynthesis in glial cells. The isolation of these compounds indicated that P. tenuipes is a promising source for producing various biologically active substances including trichothecanes. It is noteworthy that trichothecane mycotoxins are present in Paecilomyces tenuipes, which is typically used in medicinal health food.