Halliwell B
Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore.
Drugs Aging. 2001;18(9):685-716. doi: 10.2165/00002512-200118090-00004.
Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
在体内，大脑中会不断产生自由基和其他所谓的“活性物质”。有些是由“化学意外事件”产生的，比如线粒体电子传递链中的电子泄漏产生超氧阴离子自由基（O2*-）。其他的则是出于有用的目的而产生，例如一氧化氮在神经传递中的作用以及活化的小胶质细胞产生O2*-。由于大脑对ATP的需求量很高，它会迅速消耗氧气，因此容易受到线粒体功能干扰的影响，而这反过来又会导致O2*-生成增加。大脑含有多种抗氧化防御机制，其中线粒体含锰超氧化物歧化酶和还原型谷胱甘肽似乎尤为重要。铁是自由基损伤的有力促进剂，能够分别催化过氧化氢和脂质过氧化物生成高反应性的羟基、烷氧基和过氧自由基。虽然大脑中的大部分铁储存在铁蛋白中，但“催化性”铁很容易从受损的脑组织中释放出来。通过一系列检测方法，在帕金森病、阿尔茨海默病和肌萎缩侧索硬化症患者的尸检组织中检测到DNA、脂质和蛋白质的氧化损伤水平升高，并且这些变化中的至少一些可能在疾病进展早期就会出现。这些疾病中发生的蛋白质积累和沉淀可能会因氧化损伤而加剧，并且反过来可能通过干扰蛋白酶体的功能导致更多的氧化损伤。事实上，已经表明蛋白酶体抑制不仅会增加蛋白质的氧化损伤水平，还会增加其他生物分子的氧化损伤水平。因此，人们进行了许多尝试来开发能够穿过血脑屏障并减少氧化损伤的抗氧化剂。天然抗氧化剂如维生素E（生育酚）、类胡萝卜素和黄酮类化合物在成年人中不容易进入大脑，而拉扎罗类抗氧化剂替拉扎特（U-74006F）似乎定位于血脑屏障。正在研发的其他抗氧化剂包括改性自旋捕获剂和O2*-的低分子量清除剂。铅化合物的一个可能来源是使用声称能改善脑功能的传统药物。关于膳食抗氧化剂对神经退行性疾病，尤其是阿尔茨海默病的发生和进展的影响知之甚少。几种已经用于治疗的药物可能通过抗氧化作用发挥其部分作用，包括司来吉兰（丙炔苯丙胺）、阿扑吗啡和硝替卡朋。
