| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學研究所 === 102 === Excessive stimulation of glutamate induces neuronal damage through receptor-mediated excitotoxicity, which is thought to be involved in chronic neurodegenerative disorders. Several studies indicated that calcium influx into the cytoplasm in SCA transgenic cell by activation of glutamate receptors and increased toxic cascades, including the disturbance of mitochondrial function and the enhancement of apoptotic pathway. Spinocerebellar ataxia (SCA) type 17, a neurodegenerative disorder, is caused by polyglutamine (polyQ) expansion (>42 glutamines) in the basal transcription factor TATA binding protein (TBP). The polyQ expansion interferes, increases protein aggregation and results in cell death. It is believed that Chinese herbal medicines (CHMs) prescription might be a new perspective for the treatment of neurodegenerative disorder. Accordingly, we proposed to identify effective compounds of CHMs protecting cells from glutamate-induced excitotoxicity in human neuroblastoma SH-SY5Y cells. We found that NH043-1 protected human neuroblastoma SH-SY5Y cells from cell death induced by glutamate-mediated excitotoxicity, attenuated the production of intracellular reactive oxygen species (ROS), and decreased the expression of Calpain-2, SBDPs and Bax/Bcl-2 ratio for 6 h, and the expressions of cleaved-caspase-9, cleaved-caspase-3 and cleaved-PARP for 24 h. NH043-1 also blocked the decrease of mitochondrial membrane potential by MSG. In nTBP/Q79-EGFP cell model, NH043-1 also showed the remarkably protective activity against the neuronal cell death and decreased the expression of cleaved-caspase-9, cleaved-caspase-3, and cleaved-PARP for 24 h. NH043-1 also inhibited the protein aggregation. In SCA17 animal model, NH043-1-treatment SCA17 mice performed better than Saline-treatment SCA17 mice on an accelerating rota-rod and footprint experiments in 5 months. NH043-1 attenuated expression of TBP protein aggregation and cleaved-caspase-3 in cerebella of SCA17 mice. The results suggest that NH043-1 could be a potential medicine in the treatment of neurodegenerative disorders (SCA17) through inhibition of glutamate-induced apoptosis via mitochondria pathway.
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