Muramatsu K, Sheldon R A, Black S M, Täuber M, Ferriero D M
Neonatal Brain Disorders Center, Department of Neurology, University of California, San Francisco, CA, USA.
Brain Res Dev Brain Res. 2000 Oct 28;123(2):119-27. doi: 10.1016/s0165-3806(00)00088-2.
Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.
尽管针对成熟神经系统的缺氧缺血性损伤已经出现了多种治疗方法，但对于发育中的神经系统，尚未有经证实有效的治疗方法。最近的研究表明，药理学阻断神经元型一氧化氮合酶（nNOS）的活性可以减轻成熟啮齿动物缺血后的损伤。我们之前已经表明，通过基因靶向破坏或用脑内注射喹啉酸进行药理学耗竭来消除nNOS神经元，可以减少缺氧缺血后的损伤。我们采用一种更简单的药理学方法，研究了全身给药的一氧化氮合酶抑制剂7-硝基吲唑（一种相对选择性的nNOS活性抑制剂）的疗效。在损伤后使用多种剂量和浓度进行给药，我们发现只有高剂量药物有保护作用的趋势。缺氧缺血后18小时和5天时，皮质中的一氧化氮合酶活性显著降低，海马体中在2小时和18小时时也显著降低。nNOS表达降低，并且在损伤后至少18小时内一直处于抑制状态。当将nNOS表达标准化为微管相关蛋白2（MAP2）表达时，皮质中在18小时时出现降低，海马体中在2小时和18小时时出现降低。这些数据表明，在早期时间点进一步抑制一氧化氮合酶活性可能不会带来实质性益处。然而，在损伤后5天时，一氧化氮合酶活性和标准化的nNOS表达在海马体（损伤最严重的区域）恢复到基线水平或更高。这些数据表明，缺氧缺血性损伤后延迟给予nNOS抑制剂可能是有益的。
