Neuroprotective Effect of Demethylsuberosin against MPP+-induced Cell Death in Neuroblastoma SH-SY5Y Cells
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2016. 8. 마응천.
- 1-Methyl-4-phenylpyridinium ion (MPP+), which is Parkinsonism-inducing neurotoxin, causes specific cell death in human neuroblastoma SH-SY5Y cells. The rapid accumulation of MPP+ in the mitochondrial matrix inhibits mitochondrial respiratory chain complex I, resulting in the depletion of adenosine triphosphate (ATP) synthesis, the trigger of apoptotic cell death pathway and the decrease of transient receptor potential channel 1 (TRPC1) protein level. In this study, we investigated the protective effect of demethylsuberosin (DMS) against MPP+-induced cell death in SH-SY5Y cells. Cudrania tricuspidata (Carr.) Bureau ex Lavallee is widely distributed over Korea, Japan and China, and its neuroprotective, anti-inflammatory and antioxidant effects have been reported. Recently it was reported that xanthones from the root bark and isoflavones from fruits of C. tricuspidata reveleaed neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cell death in SH-SY5Y cells. However, the effect of DMS isolated from the root of C. tricuspidata against MPP+-induced cell death remains unknown. In this study, the effect of DMS isolated from the root of C. tricuspidata on MPP+-induced cell death were investigated. DMS protected neuronal cells against MPP+-induced cell death, and its protective effect was much better than the positive control, betulinic acid. It has been reported that MPP+ triggers apoptotic cell death pathway such as increase of Bax and decrease of Bcl-2. In this study, we identified that DMS inhibited the MPP+-induced apoptotic cell death pathway. Furthermore, DMS attenuated the MPP+-induced dysfunction of the chymotrypsin-like and caspase-like activities of proteasome in SH-SY5Y cells, and its restorable effect was much better than betulinic acid. DMS attenuated the MPP+-induced decrease of TRPC1 protein, associated with store-operated Ca2+ channels. The MPP+-induced decrease of TRPC1 protein lead to reduce thapsigargin-stimulated Ca2+ influx in cells, and this can cause cell death. DMS also attenuated the reduction of thapsigargin-stimulated Ca2+ influx in cells. These results suggest that DMS could have helpful effects on MPP+-induced cell toxicity by up-regulating TRPC1 protein level.