Neuroprotective effects of the stable nitroxide compound Tempol on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in the Nerve Growth Factor-differentiated model of pheochromocytoma PC12 cells
Neuroprotective effects of the stable nitroxide compound Tempol on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in the Nerve Growth Factor-differentiated model of pheochromocytoma PC12 cells
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DOI：
10.1016/j.ejphar.2006.08.022
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发表时间：
2006-11-07
影响因子：
5
通讯作者：
Lazarovici, Philip
中科院分区：
文献类型：
--
作者：
Lipman, Tatiana;Tabakman, Rinat;Lazarovici, Philip
用神经生长因子（NGF）诱导的嗜铬细胞瘤PC 12细胞暴露于MPP+毒素诱导的帕金森病（PD）模型，研究自由基清除剂和超氧化物歧化酶模拟物4-羟基-2，2，6，6-四甲基哌啶-n-氧基（Tempol）的神经保护作用。MPP+诱导的PC 12细胞死亡在暴露于1.5 mM MPP+后72 h通过释放乳酸脱氢酶、半胱天冬酶-3活化和刺激存活和应激丝裂原活化蛋白激酶来测量。将PC 12细胞暴露于MPP+激活ERK 1和ERK 2（72 h后为对照的40倍）、JNK 1和JNK 2（48 h后为4倍）和p-38 α（24 h后为10倍）。用500 μ M Tempol预处理PC 12细胞，在诱导MPP+损伤前1小时，使LDH释放到培养基中减少70%，抑制caspase-3活性30%，改善线粒体功能33%，其作用与ERK 1和ERK 2磷酸化活性减少70%相关。这些发现支持Tempol在MPP+诱导的PC 12细胞死亡模型中的神经保护作用及其作为治疗帕金森病的潜在药物的用途。(c)2006 Elsevier B. V.保留所有权利。
Nerve growth factor (NGF) differentiated pheochromocytoma PC12 cells exposed to 1-methyl-4-phenylpyridinium (MPP+) toxin were used as an in vitro pharmacological model of Parkinson's disease to examine the neuroprotective effects of 4-hydroxy-2,2,6,6-tetramethyl piperidine-n-oxyl (Tempol), a free radical scavenger and a superoxide dismutase-mimetic compound. MPP+-induced PC 12 cell death was measured 72 h after exposure to 1.5 mM MPP+ by the release of lactate dehydrogenease, caspase-3 activation and stimulation of survival and stress mitogen-activated protein kinases. Exposure of PC12 cells to MPP+ activated ERK1 and ERK2 (forty-fold over control after 72 h), JNK1 and JNK2 (fourfold after 48 h) and p-38 alpha (tenfold after 24 h). Pretreatment of PC12 cells with 500 mu M Tempol, 1 h before induction of the MPP+ insult, reduced by 70% the release of LDH into the medium, inhibited caspase-3 activity by 30% and improved by 33% mitochondrial function, effects correlated with a 70% reduction in ERK1 and ERK2 phosphorylation activity. These findings support the neuroprotective effect of Tempol in the MPP+-induced PC12 cell death model and its use as a potential drug for treatment of Parkinson's disease. (c) 2006 Elsevier B.V. All rights reserved.