NEUROPROTECTIVE FUNCTION OF GAMMA TOCOPHEROL

最近来自多个实验室的研究表明，酶衍生的反应氮物种(RNS)是阿尔茨海默病(AD)大脑以及其他不同医疗条件下的主要神经毒性应激，包括感染性休克、心血管疾病和肌萎缩侧索硬化症(ALS)。我们专门测量了蛋白质和脂肪的硝化作用，我们的发现引导我们假设，硝化损伤是阿尔茨海默病的一个关键因素。导致这一假说的发现如下。(1)蛋白质硝化产物，特别是3-硝基-酪氨酸(3N02-Tyr)，在发现经典AD组织病理学的AD大脑区域中增加2-7倍，但在小脑中则不增加，小脑在AD中相对较多。(2)脂质硝化产物，特别是5-硝基-γ-生育酚(5-NO2-γ-toc)，在AD大脑的受累区域相应增加。脂肪硝化特别严重，在AD时，总的γ-生育酚(γ-TOC)池的10%-40%被硝化。(3)当对AD脑组织进行分级研究时，发现线粒体脂比整体脂更容易硝化。(4)我们发现，控制诱导型一氧化氮合酶(INOS)表达的p38丝裂原活化蛋白激酶在AD大脑的受累区域处于高激活状态。激活的p38被发现与疾病的经典组织病理学特征(斑块和缠结)有关，其中广泛的蛋白质硝化已被证明是定位的。这些发现进一步表明，γ-生育酚(Gamma-toc)，一种自然产生的α-生育酚(α-toc，维生素E)的同系物，可能作为人脑中RNS的清道夫起到了迄今未被认识的保护作用。这种可能性与AD的临床治疗密切相关，因为α-生育酚现在被广泛用于减缓AD的进展，而补充γ-生育酚还没有被研究过。这些观察阐明了氧化应激和神经炎症之间的关系，并为潜在的AD新疗法提供了直接的建议。

Recent studies from a number of laboratories implicate enzymatically- derived reactive nitrogen species (RNS) as a major neurotoxic stress in the Alzheimer's disease (AD) brain, as well as in other diverse medical conditions including septic shock, cardiovascular disease and amyotrophic lateral sclerosis (ALS). We have specifically measured protein and lipid nitration and our findings lead us to hypothesize that nitrative damage is a key factor in Alzheimer's disease. The findings that lead to this hypothesis are as follows. (1) Protein nitration products, specifically 3-nitro-tyrosine (3N02-Tyr) are increased 2-7 fold in regions of the AD brain where classical AD histopathology is found, but not in the cerebellum, which is relatively spaed in AD. (2) Lipid nitration products, specifically 5-nitro-gamma-tocopherol (5-NO2-gamma-toc), are correspondingly increased in affected regions of the AD brain. Lipid nitration is particularly severe, with 10-40% of the total gamma- tocopherol (gamma-toc) pool being nitrated in AD. (3) When fractionation studies are performed on AD brain tissue, mitochondrial lipids are found to be more heavily nitrated than bulk lipids. (4) We have discovered that the p38 mitogen-activated protein kinase, which controls the expression of the inducible nitric oxide synthase (iNOS) enzyme, is hyperactivated in affected regions of the AD brain. Activated p38 is found in association with the classical histopathological features of the disease (plaques and tangles) where extensive protein nitration has been shown to localize. These findings further suggest that gamma-tocopherol (gamma-toc), a naturally-occurring homolog of alpha-tocopherol (alpha- toc, vitamin E) may serve a heretofore unrecognized, protective function as a scavenger of RNS in the human brain. This possibility is highly germane to the clinical treatment of AD because alpha-tocopherol is now widely used in attempts to slow the progression of AD, while gamma- tocopherol supplementation has not been investigated. These observations clarify the relationship between oxidative stress and neuroinflammation, and offer immediate suggestions as to potentially new therapies for AD.