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남은주,YoungJaeLee,YoungAhOh,JinAhJung,임혜인,SeongEunKoh,SunghoMaeng,WanSeokJoo,김용식 대한약리학회 2003 The Korean Journal of Physiology & Pharmacology Vol.7 No.6
3-Nitropropionic acid (3-NP) inhibits electron transport in mitochondria, leading to a metabolic failure. In order to elucidate the mechanism underlying this toxicity, we examined a few biochemical changes possibly involved in the process, such as metabolic inhibition, generation of reactive oxygen species (ROS), DNA strand breakage, and activation of Poly (ADP-ribose) polymerase (PARP). Exposure of SK-N-BE (2) C neuroblastoma cells to 3-NP for 48 h caused actual cell death, while inhibition of mitochondrial function was readily observed when exposed for 24 h to low concentrations (0.2~2 mM) of 3-NP. The earliest biochemical change detected with low concentration of 3-NP was an accumulation of ROS (4 h after 3-NP exposure) followed by degradation of DNA. PARP activation by damaged DNA was also detectable, but at a later time. The accumulation of ROS and DNA strand breakage were suppressed by the addition of glutathione or N-acetyl-L-cysteine (NAC), which also partially restored mitochondrial function and cell viability. In addition, inhibition of PARP also reduced the 3-NP-induced DNA strand breakage and cytotoxicity. These results suggest that oxidative stress and activation of PARP are the major factors in 3-NP-induced cytotoxicity, and that the inhibition of these factors may be useful in protecting neuroblastoma cells from 3-NP-induced toxicity.
Ceramide is involved in MPP+-induced Cytotoxicity in HumanNeuroblastoma Cells
남은주,Hye-SookLee,YoungJaeLee,Wan-SeokJoo,SunghoMaeng,임혜인,Chan-WoongPark,김용식 대한약리학회 2002 The Korean Journal of Physiology & Pharmacology Vol.6 No.6
To understand the cytotoxic mechanism of MPP+, we examined the involvement of ceramide in MPP+ -induced cytotoxicity to human neuroblastoma SH-SY5Y cells. When SH-SY5Y cells were exposed to MPP+,MPP+ induced dose-dependent cytotoxicity accompanied by 2-fold elevation of intracellular ceramide levels in SH-SY5Y cells. Three methods were used to test the hypothesis that the elevated intracellular ceramide is related to MPP+-induced cytotoxicity: C2-ceramide was directly applied to cells, sphingomyelinase (SMase) was exogenously added, and oleoylethanolamine (OE) was used to inhibit degradation of ceramide. Furthermore, inhibition of ceramide-activated protein phosphatase (CAPP), the effector of ceramide, using okadaic acid (OA) attenuated cell death but treatment of fumonisin B1, the ceramide synthase inhibitor, did not alter the cytotoxic effect of MPP+. Based on these, we suggest that the elevation of intracellular ceramide is one of the important mediators in MPP+ -induced cell death.