Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide
Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide
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DOI：
10.1016/s0304-4165(00)00181-1
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发表时间：
2001-02-16
影响因子：
3
通讯作者：
Adams, JD
中科院分区：
文献类型：
--
作者：
Klaidman, LK;Mukherjee, SK;Adams, JD
吡啶核苷酸由于其在还原反应和能量学中的作用而在氧化应激期间是关键的。本研究的目的是研究吡啶核苷酸的变化后，小鼠脑室内注射的氧化应激诱导剂，叔丁基过氧化氢（t-BuOOH）在6个脑区。第二个目的是研究NAD（+）水平和DNA片段化之间的相关性。在这里，我们证明了t-BuOOH在大多数脑区诱导NADPH的快速氧化和NAD（+）的缓慢消耗。在五个脑区也出现了轻微的NADH增加。NAD（+）耗竭与DNA片段化增加有关。这表明死亡级联反应的启动涉及聚（ADP-核糖）聚合酶（PARP）、NAD（+）、ATP耗竭和随后的脑组织细胞死亡。氧化应激20分钟后，PARP活性在某些脑区加速。为了抵消氧化应激诱导的毒性，使用腹膜内注射烟酰胺增加脑中的NAD（+）水平。过量的大脑NAD（+）阻止了某些大脑区域的DNA片段化。烟酰胺给药还导致某些区域的脑NADH、NADP（+）和NADPH水平升高。它们的合成在氧化应激期间进一步上调。烟酰胺作为NAD（+）的前体可能为神经退行性疾病的治疗提供一种有用的治疗策略。(C)2001 Elsevier Science B. V.保留所有权利。
Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD(+) levels and DNA fragmentation. Here, we demonstrate that t-BuOOH induced a rapid oxidation of NADPH and a slow depletion of NAD(+) in most brain regions. A slight increase in NADH also occurred in five brain regions. NAD(+) depletion was associated with increased DNA fragmentation. This suggests the initiation of a death cascade involving poly(ADP-ribose) polymerase (PARP), NAD(+), ATP depletion and consequent cell death in brain tissue. PARP activity was accelerated in some brain regions after 20 min of oxidative stress. To counteract oxidative stress induced toxicity, NAD(+) levels were increased in the brain using an intraperitoneal injection of nicotinamide. A surplus of brain NAD(+) prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher brain NADH, NADP(+) and NADPH levels in some regions. Their synthesis was further upregulated during oxidative stress. Nicotinamide as a precursor for NAD(+) may provide a useful therapeutic strategy in the treatment of neurodegeneration. (C) 2001 Elsevier Science B.V. All rights reserved.