Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity
Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity
复制标题
DOI：
10.1111/j.1471-4159.2009.06266.x
复制
发表时间：
2009-09-01
影响因子：
4.7
通讯作者：
Donzelli, Sonia
中科院分区：
文献类型：
--
作者：
Choe, Chi-un;Lewerenz, Jan;Donzelli, Sonia
氮氧自由基（HNO）供体化合物作为有效的血管舒张剂，在心血管系统中起作用，改善心肌收缩力并减少缺血-再灌注损伤。就神经系统而言，HNO供体已被证明可以减弱NMDA受体活性和神经元损伤，这表明其产生可能对脑缺血性损伤具有保护作用。因此，我们研究了经典的HNO供体，Angeli的盐（AS），对脑缺血/再灌注损伤的实验性中风的小鼠模型和相关的体外神经毒性范例的影响。I.在大脑中动脉闭塞之前，在小鼠中p.注射AS（40 μ mol/kg）使皮质梗死面积加重，并使持续性神经功能缺损恶化。AS不仅降低收缩压，而且还诱导体内全身氧化应激，表现为尿和血清中异前列烷水平升高。在体外，神经元损伤诱导的成熟神经元培养物的氧-葡萄糖剥夺加剧AS，虽然没有直接影响谷氨酸兴奋毒性。最后，AS加剧了氧化性谷氨酸毒性，即在缺乏离子型谷氨酸受体的未成熟神经元中通过氧化应激传播的细胞死亡。两者合计，我们的数据表明，HNO可能会恶化脑缺血再灌注损伤，通过增加氧化应激和减少脑灌注的浓度显示在体内心脏保护。
Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I. p. injection of AS (40 mu mol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.