Pharmacological shift of the ambiguous nitric oxide action from neurotoxicity to cyclic GMP-mediated protection
Pharmacological shift of the ambiguous nitric oxide action from neurotoxicity to cyclic GMP-mediated protection
复制标题
模糊一氧化氮作用从神经毒性到环 GMP 介导的保护的药理学转变
作者：
Shigeru Kohgami;T. Ogata;T. Morino;Haruyasu Yamamoto;P. Schubert
摘要目标：利用一种新开发的脊髓神经元一氧化氮损伤模型，检测细胞内环磷酸鸟苷（GMP）增加对神经元损伤的影响。研究方法：一氧化氮（NO）供体硝普钠（SNP）暴露24小时后，通过测定损伤神经元释放的乳酸脱氢酶活性来评价神经元损伤。结果如下：氧自由基清除剂具有保护作用，表明10 μM SNP引起的神经元损伤主要是由于过氧亚硝酸盐的形成。另外，通过加入100 μM 8-溴环GMP导致的细胞内环GMP增加，也可以实现对NO诱导的损伤的强烈抑制。丙戊茶碱（Propentofylline，PPF，1-100 μM）是一种黄嘌呤衍生物和选择性磷酸二酯酶（PDE）抑制剂，可增强SNP诱导的细胞内cGMP升高。1 μ MPPF可完全阻断10 μM SNP作用24 h引起的神经元损伤。讨论内容：这些结果表明，NO有一个模棱两可的行动，即有毒的，有利于形成，但保护细胞内的环GMP升高，可以加强PDE抑制。因此，PDE抑制剂，如PPF，可能是有用的治疗药物，以限制中枢神经系统中的氧化神经元损伤。
Abstract Objectives: The effect of intracellular cyclic guanosine monophosphate (GMP) increase on neuronal damage was tested using a newly developed nitric oxide-related injury model of cultured spinal cord neurons. Methods: Neuronal damage after 24-hour-exposure to sodium nitroprusside (SNP), a nitric oxide (NO) donor, was evaluated by measuring the activity of released lactate dehydrogenase from injured neurons. Results: Oxygen radical scavengers had a protective effect, indicating that the neuronal damage, elicited by 10 μM SNP, was largely due to peroxynitrite formation. Alternatively, a strong inhibition of the NO-induced damage could also be achieved by an intracellular cyclic GMP increase resulting from the addition of 100 μM 8-bromo-cyclic GMP. Propentofylline (PPF, 1–100 μM), a xanthine derivative and rather selective phosphodiesterase (PDE) inhibitor, enhanced intracellular cyclic GMP elevation induced by SNP exposure. The neuronal damage induced by 10 μM SNP exposure for 24 hours was almost completely blocked in the presence of 1 μM PPF. Discussion: These results suggest that NO has an ambiguous action, i.e. toxic by favoring the formation of, but protective by intracellular cyclic GMP elevation which can be reinforced by PDE inhibition. Therefore, PDE inhibitors, such as PPF, may be useful therapeutic drugs to limit oxidative neuronal damage in the central nervous system.
一氧化氮、超氧化物和过氧亚硝酸盐：好的、坏的和丑陋的。
DOI：
10.1152/ajpcell.1996.271.5.c1424
发表时间：
1996
期刊：
The American journal of physiology
影响因子：
--
作者：
Beckman,JS;Koppenol,WH
通讯作者：
Koppenol,WH
影响因子：
3.7
作者：
Küpper, H;Küpper, FC;Spiller, M
通讯作者：
Spiller, M