抗氧化剂或可干扰阿尔茨海默病进程
2012-04-12 14:06:31   来源： 丁香园   作者：  评论：0 点击：

科学日报（2012.4.10）——阿尔海默茨（AD）现为美国第六大死亡原因，有将近1/8 的超过65岁人群患有此病。目前并没有任何一种治疗方法可改变疾病的进程。然而，越来越多的证据显示，在AD症状开始出现的几年前，机体操控铁和其他金属 （如铜和锌）方式就可能发生了改变。新的研究也显示，血浆中铁含量的减少或可保护大脑免受AD所引起相关的改变。

在 由OthmanGhribi博士（北达科塔大学医药健康学院药理学、生理学和治疗学系副教授）领导的调查小组的最新研究中，给兔子予高胆固醇饮食喂养，可 使兔子积累出被称为β淀粉样蛋白的小分子蛋白斑块。这些斑块对神经元有毒性作用，并促使阿尔海默茨病的发展。同时，这些兔子的tau蛋白也发生了改变，它 可作为神经元骨架结构的一部分。当这种蛋白发生严重磷酸化时，神经元传导电信号的功能将受到干扰。随后用被称为去铁酮（deferiprone，铁螯合 剂）的药物治疗，兔子血浆铁含量可下降，而且大脑中β淀粉样蛋白和磷酸化tau蛋白含量也回到正常水平。

另一参与AD退化进程的是活性氧自由基产物，它可损害大脑神经元。去铁酮也被看作可抑制由血液中游离铁引起的氧自由基损伤。然而在这个研究的治疗组中，活性氧自由基并无差异。在AD患者大脑出现铁的异常分布——特别是在β淀粉样蛋白斑块核心积累到很高水平，在这样的环境中更容易起反应。

据 Ghribi博士所述，“我们的数据表明，铁螯合剂去铁酮的治疗可抵制几种由富含胆固醇饮食所致的病理改变，去铁酮也能减少ẞ-淀粉样蛋白的产生和降低磷 酸化tau蛋白水平。”虽然对ROS水平未产生影响，但他认为，“更高剂量的去铁酮，或去铁酮与预防ROS产生的抗氧化剂联用或许能够更加完全地保护其免 受与AD病理有关的富含胆固醇饮食的有害影响。”

澳大利亚墨尔本心理卫生研究所著名阿尔海默茨病金属代谢研究专家AshleyBush博士补充说，“这个研究以胆固醇为例，突出金属离子在作为阿尔海默茨病风险因素的毒性作用的关键调节器的角色，以这些金属间作用为靶向目标药物有望成为改变疾病的药剂。”
Antioxidant May Disrupt Alzheimer's Disease Process

ScienceDaily (Apr. 10, 2012) — Alzheimer's disease (AD) is now the sixth leading cause of death among Americans, affecting nearly 1 in 8 people over the age of 65. There is currently no treatment that alters the course of this disease. However, an increasing amount of evidence suggests that changes in the way the body handles iron and other metals like copper and zinc may start years before the onset of AD symptoms. A new study shows that reducing iron levels in blood plasma may protect the brain from changes related to AD.
In the current study a group of investigators from led by Dr. Othman Ghribi, PhD, Associate Professor, Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, rabbits were fed a high-cholesterol diet which caused them to accumulate plaques of a small protein called beta-amyloid (Aẞ). These plaques are toxic to neurons and central to the development of Alzheimer's disease. The rabbits also developed changes in tau protein, which is part of the skeleton of neurons. When this protein becomes heavily phosphorylated, the ability of neurons to conduct electrical signals is disrupted. Following treatment with a drug called deferiprone (an iron chelator), the iron level in the rabbits' blood plasma was reduced and the levels of both beta-amyloid and phosphorylated tau in the brain were returned to normal levels.

Another degenerative process in AD involves the production of reactive oxygen species (ROS) that can damage neurons in the brain. Deferiprone is also thought to suppress this reactive oxygen damage caused by free iron in the bloodstream, however in this study there was no difference in reactive oxygen species in the treated group. It appears that iron in the AD brain is located in the wrong places -- in particular it accumulates to very high levels in the cores of beta-amyloid plaques and is very reactive in this setting.

According to Dr. Ghribi, "Our data show that treatment with the iron chelator deferiprone opposes several pathological events induced by a cholesterol-enriched diet…Deferiprone reduced the generation of Aẞ and lowered levels of tau phosphorylation." While there was no effect on ROS levels, he comments that "It is possible that a higher dose of deferiprone, or combination therapy of deferiprone together with an antioxidant to prevent ROS generation would more-fully protect against the deleterious effects of cholesterol-enriched diet that are relevant to AD pathology."

Noted expert on metals metabolism research on AD Ashley Bush, MD, PhD, Mental Health Research Institute, Melbourne, Australia, adds that "this research highlights the role of metal ions as key modulators for the toxic interactions of risk factors for Alzheimer's disease, in this case cholesterol. Drugs targeting these metal interactions hold promise as disease-modifying agents."