RESUMEN
Abnormal levels of mammalian target of rapamycin (mTOR) signaling have been recently implicated in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD). However, the implication of mTOR in diabetes mellitus (DM)-related cognitive dysfunction still remains unknown. In the present study, we found that phosphorylated mTOR at Ser2448, phosphorylated p70S6K at Thr421/Ser424 and phosphorylated tau at Ser396 were significantly increased in the hippocampus of streptozotocin (STZ)-induced diabetic mice when compared with control mice. A low dose of rapamycin was used to elucidate the role of mTOR signaling in DM-related cognitive deficit. Rapamycin restored abnormal mTOR/p70S6K signaling and attenuated the phosphorylation of tau protein in the hippocampus of diabetic mice. Furthermore, the spatial learning and memory function of diabetic mice significantly impaired compared with control mice, was also reversed by rapamycin. These findings indicate that mTOR/p70S6K signaling pathway is hyperactive in the hippocampus of STZ-induced diabetic mice and inhibiting mTOR signaling with rapamycin prevents the DM-related cognitive deficits partly through attenuating the hyperphosphorylation of tau protein.
Asunto(s)
Trastornos del Conocimiento/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipocampo/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas tau/metabolismo , Animales , Trastornos del Conocimiento/etiología , Diabetes Mellitus Experimental/complicaciones , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacologíaRESUMEN
In the crystal structure of the title compound, C16H14F3N3OS·C3H8O, the mol-ecules are linked into chains along [010] via N-Hâ¯O and O-Hâ¯N hydrogen bonds. The triclinic form was reported by Ren et al. [(2011). Acta Cryst. E67, o270] and the first monoclinic form by Chen et al. [(2012). Acta Cryst. E68, o2015-o2016]. The fused five-and six-membered rings make a dihedral angle of 1.22â (2)°, while the benzene and pyridine rings make a dihedral angle of 10.15â (2)°.