Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells
Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells
复制标题
DOI：
10.1124/jpet.104.065300
复制
发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Dohi, T
中科院分区：
文献类型：
--
作者：
Morioka, N;Kumagai, K;Dohi, T
在这项研究中，我们研究了非甾体抗炎药（NSAID）对1-甲基-4-苯基吡啶（MPP+）诱导的PC 12细胞死亡的影响。将PC 12细胞与吲哚美辛、布洛芬、酮洛芬或双氯芬酸共孵育，但不与阿司匹林或N-[2-（环己氧基）-4-硝基苯基]甲磺酰胺（NS-398）共孵育，显著增强MPP+诱导的细胞死亡。相反，这些NSAID对鱼藤酮诱导的细胞死亡没有影响。这些NSAID的增强作用不受自由基清除剂苯基-N-丁基硝酮、抗氧化剂N-乙酰基-L-半胱氨酸、选择性半胱天冬酶-3抑制剂Ac-DEVD-CHO或过氧化物酶体增殖物激活受体γ的选择性拮抗剂2-氯-5-硝基-N-苯基苯甲酰胺（GW 9662）的抑制。此外，我们观察到，DNA片段，这是细胞凋亡的标志之一，没有诱导MPP+和NSAID的共孵育。我们证实，30 μ M MPP+和100 μ M吲哚美辛，布洛芬，酮洛芬，或双氯芬酸的PC 12细胞共孵育导致细胞内MPP+的积累显着增加与孵育30 μ M MPP+单独。此外，这些NSAID显着减少MPP+从PC 12细胞的流出。（3-（3-（2-（7-氯-2-喹啉基）乙烯基）苯基（（3-二甲基氨基-3-氧代-丙基）硫基）甲基）丙酸（MK 571）是一种多药耐药蛋白（MRP）抑制剂，其模拟NSAID诱导的作用，增加细胞毒性并促进MPP+积累。此外，在PC 12细胞中还检测到了某些类型的MRPs mRNA。这些结果表明，某些NSAID可能通过阻断MRP抑制反向转运，导致MPP+诱导的细胞死亡增强，从而导致MPP+细胞内蓄积显著增加。
In this study, we investigated the effects of nonsteroidal anti-inflammatory drugs ( NSAIDs) on 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in PC12 cells. Coincubation of PC12 cells with indomethacin, ibuprofen, ketoprofen, or diclofenac, but not aspirin or N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide (NS-398), significantly potentiated the MPP+-induced cell death. In contrast, these NSAIDs had no effect on rotenone-induced cell death. The potentiating actions of these NSAIDs were not suppressed by treatment with phenyl-N-butylnitrone, a radical scavenger; N-acetyl-L-cysteine, an antioxidant; Ac-DEVD-CHO, a selective caspase-3 inhibitor; or 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective antagonist of peroxisome proliferator-activated receptor gamma. Furthermore, we observed that DNA fragmentation, which is one of the hallmarks of apoptosis, was not induced by coincubation with MPP+ and NSAIDs. We confirmed that coincubation of PC12 cells with 30 muM MPP+ and 100 muM indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP+ compared with incubation with 30 muM MPP+ alone. In addition, these NSAIDs markedly reduced the efflux of MPP+ from PC12 cells. (3-(3(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid (MK 571), which is an inhibitor of multidrug resistance proteins (MRPs), mimicked the NSAIDs-induced effects, increasing cell toxicity and promoting the accumulation of MPP+. Moreover, some types of MRPs' mRNA were detected in PC12 cells. These results suggest that some NSAIDs might cause a significant increase in the intracellular accumulation of MPP+ via the suppression of reverse transport by the blockade of MRP, resulting in the potentiation of MPP+-induced cell death.