PATHWAYS INVOLVED IN THE GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES DURING GLUCOSE DEPRIVATION AND ITS ROLE ON THE DEATH OF CULTURED HIPPOCAMPAL NEURONS
PATHWAYS INVOLVED IN THE GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES DURING GLUCOSE DEPRIVATION AND ITS ROLE ON THE DEATH OF CULTURED HIPPOCAMPAL NEURONS
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DOI：
10.1016/j.neuroscience.2010.02.074
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发表时间：
2010-06-02
期刊：
影响因子：
3.3
通讯作者：
Massieu, L.
中科院分区：
文献类型：
--
作者：
Paramo, B.;Hernandez-Fonseca, K.;Massieu, L.
氧化应激已被认为是导致低血糖引起的神经元死亡的机制，并且已观察到低血糖发作期间反应性物质（RS）的早期产生。然而，活性氧（ROS）和氮（RNS）物种的来源尚未完全确定。在本研究中，我们已经研究了各种酶途径的RS生产和神经元死亡诱导的葡萄糖剥夺（GD）在海马培养的贡献。我们观察到GD期间RS迅速增加，这取决于NMDA和非NMDA受体的激活以及细胞外间隙钙的内流。因此，在GD期间，细胞内钙浓度[Ca2 +]（i）逐渐增加超过30倍。据观察，通过激活钙依赖性酶磷脂酶A（2）（cPLA（2））和黄嘌呤氧化酶（XaO）产生的超氧化物有助于神经元损伤，而一氧化氮合酶（NOS）显然不参与。抑制cPLA（2）可降低GD早期的RS，而抑制XaO则可降低GD晚期的RS。抗氧化剂trolox和ebselen也显示出对神经元死亡和减少RS生成的保护作用。NADPH氧化酶的抑制也有助于超氧化物的早期产生。总之，本研究结果表明，早期激活的钙依赖性活性氧产生途径参与神经元死亡与葡萄糖剥夺。(C)2010年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Oxidative stress has been suggested as a mechanism contributing to neuronal death induced by hypoglycemia, and an early production of reactive species (RS) during the hypoglycemic episode has been observed. However, the sources of reactive oxygen (ROS) and nitrogen (RNS) species have not been fully identified. In the present study we have examined the contribution of various enzymatic pathways to RS production and neuronal death induced by glucose deprivation (GD) in hippocampal cultures. We have observed a rapid increase in RS during GD, which depends on the activation of NMDA and non-NMDA receptors and on the influx of calcium from the extracellular space. Accordingly, intracellular calcium concentration [Ca2+](i) progressively increases more than 30-fold during the GD period. It was observed that superoxide production through the activation of the calcium-dependent enzymes, phospholipase A(2) (cPLA(2)) and xanthine oxidase (XaO), contributes to neuronal damage, while nitric oxide synthase (NOS) is apparently not involved. Inhibition of cPLA(2) decreased RS at early times of GD whereas inhibition of XaO diminished RS at more delayed times. The antioxidants trolox and ebselen also showed a protective effect against neuronal death and diminished RS generation. Inhibition of NADPH oxidase also contributed to the early generation of superoxide. Taking together, the present results suggest that the early activation of calcium-dependent ROS producing pathways is involved in neuronal death associated with glucose deprivation. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.