CAM Antioxidants and ALS

在过去的十年里，由于营养的改善，肌萎缩侧索硬化症患者的生活质量有了显著的提高， 呼吸支持和各种补充和替代药物(CAM)。肌萎缩侧索硬化症患者的CAM 被传统医学界广泛接受。我们的长期目标是找到一个组合 延缓定义肌萎缩侧索硬化症的运动神经元进行性死亡的治疗行动，使这一致命的 将疾病转变为类似于脊髓灰质炎后综合症的慢性疾病。一条重要的线索来自于发现 抗氧化剂铜、锌超氧化物歧化酶的突变导致2-3%的ALS患者。我们发现 突变有利于超氧化物歧化酶的锌流失，通过增加亚硝酸盐对运动神经元产生毒害作用 应激，提示锌状态可以将2%的家族性SOD患者与其余98%的ALS联系起来 病人。我们的研究还表明，运动神经元周围的星形胶质细胞中的负性应激 导致运动神经元的进行性死亡。ALS突变型超氧化物歧化酶在转基因小鼠中的表达 大鼠现在被广泛用于研究传统疗法和CAM疗法对生存的影响。使用 为了更好地了解SOD故障是如何导致ALS的，我们发现了几个新的CAM 可以调节肌萎缩侧索硬化症进展的抗氧化疗法。使用细胞培养和 转基因大鼠脊髓的显微分析方法，我们将表征CAM治疗的能力 来调节这些动物的疾病进展。我们的第一个目标是确定锌是否可以延缓 转基因SOD大鼠肌萎缩侧索硬化症的进展及重金属螯合治疗是否无意中可能 通过去除锌来加速肌萎缩侧索硬化症。我们的第二个目标将表征抗坏血酸的消耗是否通过 缺乏锌的超氧化物歧化酶使脊髓容易受到α-生育酚缺乏的影响。我们的最终目标是 硫辛酸是否可以改善α-生育酚缺乏的影响或减少毒性 超氧化物歧化酶对衰老大鼠的影响。我们提议的研究将为研究CAM如何 抗氧化剂治疗可以协调起来，以调节ALS的过程。

The quality of life of ALS patients has substantially improved in the past decade from better nutrition, respiratory support and a variety of complementary and alternative medicines (CAM). CAM for ALS patients is well accepted by the traditional medical community. Our long-term goal is to find a combination of therapeutic actions to slow the progressive death of motor neurons that defines ALS, turning this fatal disease into a chronic condition resembling post-polio syndrome. An important clue came from discovering mutations to the antioxidant copper, zinc superoxide dismutase cause 2-3% of ALS patients. We found that the loss of zinc from SOD, which is favored by the mutations, is toxic to motor neurons by increasing nitrative stress, suggesting zinc status could link the 2% familial SOD patients with the remaining 98% of ALS patients. Our research has also shown that nitrative stress in astrocytes surrounding motor neurons contributes to the progressive death of motor neurons. Expression of ALS-mutant SODs in transgenic mice and rats is now widely used to study the effects of both traditional as well as CAM therapies on survival. With a better understanding of how SOD malfunctions to cause ALS, we have identified several novel CAM antioxidant therapies that could modulate the progression of ALS. Using a combination of cell culture and microanalytical methods of spinal cord from transgenic rats, we will characterize the ability of CAM therapies to modulate disease progression in these animals. Our first aim is to determine whether zinc can slow the progression of ALS in transgenic SOD rats and whether heavy metal chelation therapy unintentionally may accelerate ALS by removing zinc. Our second aim will characterize whether the depletion of ascorbate by zinc deficient SOD makes the spinal cord vulnerable to a-tocopherol deficiencies. Our final aim will characterize whether lipoic acid can ameliorate the effects of a-tocopherol deficiency or reduce the toxic effects of SOD in aging rats. Our proposed studies will provide a mechanistic basis for examining how CAM antioxidant therapies can be coordinated to modulate the course of ALS.