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BRAIN OXIDATIVE STRESS--A SIGN OF AGING OR EMINENT DEATH

大脑氧化应激——衰老或死亡的迹象

基本信息

批准号：
6195289
负责人：
MOSTAFA Zaki BADR
金额：
$ 7.25万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2002-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6195289
关键词：
aging antioxidants arachidonate biomarker brain disorders death enzyme activity glutathione peroxidase laboratory rat mass spectrometry neural degeneration omega 3 fatty acid oxidative stress superoxide dismutase

项目摘要

Brain oxidative stress is reported to play an important role in the process of aging and aging-related neurodegenerative diseases. Using conventional markers however, studies have produced conflicting data concerning the level of brain oxidative injury in aged animals. The purpose of this study is to further investigate the relationship between brain oxidative stress and aging, using novel sensitive markers which reflect differential contribution of various brain regions and cell types. Recently, F2-isoprostanes and F4-neuroprostanes, nonenzymatic oxidative products of arachidonic and docosahexaenoic acids, respectively, have been identified as novel and sensitive markers of oxidative injury. Preliminary data show that among all animal groups studied (Male Fischer 344 rats of 4,10,50, and 100 weeks old), only a subpopulation (4 out of 8) of 50 week old rats exhibited high brain neuroprostane levels. Based on these data, we hypothesize that brain oxidative damage is linked to death than to aging. This hypothesis is supported by the fact that the incidence of high brain neuroprostanes observed in 50 percent of studied animals is identical to the death rates reported for this strain at this age, and that mean brain neuroprostane levels were significantly lower in the 100 week old rats, compared with the 50 week old rat group. Our hypothesis will be tested by pursuing the following specific aims: (1) Confirm the exact incidence of high brain neuroprostane levels among male Fischer 344 rats of various ages, (2) Establish whether isoprostanes and neuroprostanes are more accurate and sensitive indicators, compared with conventional markers, of brain "oxidative status", and (3) Localize sources of oxidative stress mediators in the brain. Free and esterified brain isoprostanes and neuroprostanes will be quantified by mass spectroscopy. Levels of brain conventional oxidative markers as well as antioxidant enzyme activities will be assessed by established biochemical methods. Since the levels of arachidonic and docosahexaenoic acids, the precursors of isoprostanes and neuroprostanes, respectively, vary significantly between different regions of the brain (white vs gray matter), as well as among different cell types (neurones, astrocytes, oligodendrocytes) and subcellular fractions (myelin, synaptosomes), these two markers may help localize brain region and/or cell types exposed to oxidative injury. Furthermore, confirming that brain oxidative stress occurs earlier in life than previously reported would suggest that senescent animals may indeed arise from an oxidative damage-resistant subpopulation of the middle age group. Consequently, early diagnosis of this condition may present the opportunity to intervene to slow or halt neuronal degeneration and aging.

脑氧化应激在衰老和与衰老相关的神经退行性疾病中起重要作用。然而，使用常规标记物，研究产生了关于老年动物脑氧化损伤水平的相互矛盾的数据。本研究的目的是进一步研究脑氧化应激和衰老之间的关系，使用新的敏感标记物，反映不同的大脑区域和细胞类型的差异贡献。最近，F2-异前列烷和F4-神经前列烷，花生四烯酸和二十二碳六烯酸的非酶氧化产物，分别已被确定为新的和敏感的氧化损伤的标志物。初步数据显示，在研究的所有动物组（4、10、50和100周龄的雄性Fischer 344大鼠）中，只有50周龄大鼠的亚群（8只中的4只）表现出高的脑神经前列腺素水平。基于这些数据，我们假设脑氧化损伤与死亡有关，而不是与衰老有关。这一假设得到以下事实的支持：在50%的研究动物中观察到的高脑神经前列烷的发生率与该品系在该年龄的死亡率相同，并且与50周龄大鼠组相比，100周龄大鼠的平均脑神经前列烷水平显著较低。我们的假设将通过追求以下具体目标进行检验：（1）确认不同年龄的雄性Fischer 344大鼠中高脑神经前列烷水平的确切发生率，（2）确定与传统标记物相比，异前列烷和神经前列烷是否是脑“氧化状态”的更准确和灵敏的指标，以及（3）定位脑中氧化应激介质的来源。游离和酯化的脑异前列烷和神经前列烷将通过质谱法定量。将通过已建立的生化方法评估脑常规氧化标志物水平以及抗氧化酶活性。由于花生四烯酸和二十二碳六烯酸（异前列烷和神经前列烷的前体）的水平在大脑的不同区域（白色与灰质）之间以及在不同细胞类型（神经元、星形胶质细胞、少突胶质细胞）和亚细胞组分（髓鞘、突触体）之间差异显著，因此这两种标记物可能有助于定位暴露于氧化损伤的大脑区域和/或细胞类型。此外，确认脑氧化应激发生在生命早期比以前报道的将表明，衰老的动物可能确实产生于中年组的抗氧化损伤亚群。因此，这种情况的早期诊断可能会提供干预以减缓或停止神经元变性和衰老的机会。