RESUMO
Autophagy is an essential cellular process concern with cellular homeostasis down-regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34cdc2 /cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP-treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.
Assuntos
Autofagia/efeitos dos fármacos , Imunossupressores/farmacologia , Intoxicação por MPTP/tratamento farmacológico , Sirolimo/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Animais , Autofagia/imunologia , Imunossupressores/química , Imunossupressores/uso terapêutico , Intoxicação por MPTP/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/imunologia , Células PC12 , Ratos , Sirolimo/uso terapêutico , Peixe-ZebraRESUMO
In this paper, a new species Sovia lii spec. nov. is described from Qinling-Daba Mountains in S. Gansu province and S. Shaanxi province, W. China. Variability of wing pattern, differences with its similar congeners and some biological information of this new taxon are introduced. External variability of Sovia lucasii, which is discovered from Shaanxi for the first time and is sympatric with the new species there, is illustrated and discussed. A brief analysis of the distributional pattern of the genus Sovia is provided. A key to the genus is given.
