The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death
The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death
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DOI：
10.1523/jneurosci.21-16-06069.2001
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发表时间：
2001-08-15
影响因子：
5.3
通讯作者：
Schubert, D
中科院分区：
文献类型：
--
作者：
Ishige, K;Chen, Q;Schubert, D
氧化应激被认为是许多CNS病理学中神经细胞死亡的原因，包括缺血、创伤和神经退行性疾病。谷氨酸通过抑制胱氨酸-谷氨酸反向转运体x（c）（-）杀死缺乏离子型谷氨酸受体的神经细胞，导致胱氨酸摄取抑制、谷胱甘肽损失和氧化应激细胞死亡途径启动。许多儿茶酚胺被发现阻断这一途径。具体而言，多巴胺和相关配体抑制谷氨酸诱导的细胞死亡，在克隆神经细胞系和大鼠皮层神经元。多巴胺D4拮抗剂可拮抗多巴胺、阿扑吗啡和阿扑可待因的保护作用，但不拮抗肾上腺素和去甲肾上腺素。多巴胺D4激动剂也具有保护作用，这种保护作用被多巴胺D4拮抗剂U101958抑制。虽然一些儿茶酚胺的保护作用与其抗氧化活性相关，但其他几种配体的保护和抗氧化活性之间没有相关性。正常情况下，谷氨酸引起活性氧（ROS）和细胞内Ca 2+的增加。阿扑吗啡部分抑制谷氨酸诱导的ROS产生，并阻断cGMP操纵的Ca 2+通道的开放，导致细胞死亡途径后期的Ca 2+升高。这些数据表明，阿扑吗啡对氧化应激诱导的细胞死亡的保护作用，至少部分，介导的多巴胺D4受体通过调节cGMP操作的Ca 2+通道。
Oxidative stress is thought to be the cause of nerve cell death in many CNS pathologies, including ischemia, trauma, and neurodegenerative disease. Glutamate kills nerve cells that lack ionotropic glutamate receptors via the inhibition of the cystine-glutamate antiporter x(c)(-), resulting in the inhibition of cystine uptake, the loss of glutathione, and the initiation of an oxidative stress cell death pathway. A number of catecholamines were found to block this pathway. Specifically, dopamine and related ligands inhibit glutamate-induced cell death in both clonal nerve cell lines and rat cortical neurons. The protective effects of dopamine, apomorphine, and apocodeine, but not epinephrine and norepinephrine, are antagonized by dopamine D4 antagonists. A dopamine D4 agonist also protects, and this protective effect is inhibited by U101958, a dopamine D4 antagonist. Although the protective effects of some of the catecholamines are correlated with their antioxidant activities, there is no correlation between the protective and antioxidant activities of several other ligands. Normally, glutamate causes an increase in reactive oxygen species (ROS) and intracellular Ca2+. Apomorphine partially inhibits glutamate-induced ROS production and blocks the opening of cGMP-operated Ca2+ channels that lead to Ca2+ elevation in the late part of the cell death pathway. These data suggest that the protective effects of apomorphine on oxidative stress-induced cell death are, at least in part, mediated by dopamine D4 receptors via the regulation of cGMP-operated Ca2+ channels.