A dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein
A dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein
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DOI：
10.1038/sj.jcbfm.9600078
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发表时间：
2005-07-01
影响因子：
6.3
通讯作者：
Ikeda, JE
中科院分区：
文献类型：
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作者：
Okada, Y;Sakai, H;Ikeda, JE
神经元凋亡抑制蛋白（NAIP/BIRC 1）是凋亡抑制蛋白（IAP）家族的成员，可抑制多种损伤诱导的神经元细胞死亡，包括缺血和中风引起的细胞死亡。本研究的目的是开发一种有效的方法来鉴定具有上调内源性NAIP能力的化合物，并确定这些化合物对缺血细胞反应的影响。建立了一种新的基于NAIP-酶联免疫吸附试验（ELISA）的体外药物筛选系统。使用该系统发现了一种多巴胺D4受体拮抗剂，称为L-745，870，具有强效NAIP上调作用。L-745，870介导的NAIP在神经元和非神经元培养细胞中的上调导致对氧化应激诱导的凋亡的脆弱性降低。通过RNA干扰技术降低NAIP表达导致L-745，870介导的氧化应激保护作用的预防。此外，在沙鼠模型中，全身给予L-745，870减轻了海马CA 1神经元的缺血诱导的损伤，并上调了挽救的海马CA 1神经元中的NAIP表达。这些数据表明，NAIP上调化合物L-745，870在急性缺血性疾病中具有治疗潜力，并且我们基于NAIP-ELISA的药物筛选可能有助于发现新的神经保护化合物。
Neuronal apoptosis inhibitory protein (NAIP/BIRC1), the inhibitor of apoptosis protein (IAP) family member, suppresses neuronal cell death induced by a variety of insults, including cell death from ischemia and stroke. The goal of the present study was to develop an efficient method for identification of compounds with the ability to upregulate endogenous NAIP and to determine the effects on these compounds on the cellular response to ischemia. A novel NAIP-enzyme-linked immunosorbent assay (ELISA)-based in vitro drug-screening system is established. Use of this system identified an antagonist of dopamine D4 receptor, termed L-745,870, with a potent NAIP upregulatory effect. L-745,870-mediated NAIP upregulation in neuronal and nonneuronal cultured cells resulted in decreased vulnerability to oxidative stress-induced apoptosis. Reducing NAIP expression via RNA interference techniques resulted in prevention of L-745,870-mediated protection from oxidative stress. Further, systemic administration of L-745,870 attenuated ischemia-induced damage of the hippocampal CA1 neurons and upregulated NAIP expression in the rescued hippocampal CA1 neurons in a gerbil model. These data suggest that the NAIP upregulating compound, L-745,870, has therapeutic potential in acute ischemic disorders and that our NAIP-ELISA-based drug screening may facilitate the discovery of novel neuroprotective compounds.