Goodman Y, Steiner M R, Steiner S M, Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
Brain Res. 1994 Aug 15;654(1):171-6. doi: 10.1016/0006-8993(94)91586-5.
Recent findings indicate that amyloid beta-peptide (A beta) can be neurotoxic by a mechanism involving an increase in the concentration of intracellular free Ca2+ ([Ca2+]i) and the generation of free radicals. In the present study, the lipoxygenase inhibitor/antioxidant nordihydroguaiaretic acid (NDGA) protected cultured rat hippocampal neurons against the toxicity of A beta in a concentration-dependent manner. Measurements of cellular oxidation (using the oxidation-sensitive dye 2,7-dichlorofluorescin) and intracellular free Ca2+ levels (using the Ca2+ indicator dye fura-2), showed that NDGA suppressed A beta-induced accumulation of reactive oxygen species (ROS) and Ca2+; Ca2+ responses to glutamate were also suppressed by NDGA. NDGA prevented neuronal injury and accumulation of ROS induced by iron, indicating a role for NDGA as an antioxidant in NDGA-mediated neuroprotection. Another lipoxygenase inhibitor (AA861) also protected against A beta and iron toxicity whereas the the 5-lipoxygenase-activating protein inhibitor L655,238 and the cyclooxygenase inhibitor indomethacin were ineffective. These findings suggest that NDGA can interupt a neurodegenerative pathway relevant to the pathophysiology of Alzheimer's disease.
最近的研究结果表明，β-淀粉样肽（Aβ）可通过一种涉及细胞内游离Ca2+（[Ca2+]i）浓度升高和自由基生成的机制产生神经毒性。在本研究中，脂氧合酶抑制剂/抗氧化剂去甲二氢愈创木酸（NDGA）以浓度依赖的方式保护培养的大鼠海马神经元免受Aβ的毒性作用。通过测量细胞氧化（使用氧化敏感染料2,7-二氯荧光素）和细胞内游离Ca2+水平（使用Ca2+指示染料fura-2）发现，NDGA可抑制Aβ诱导的活性氧（ROS）和Ca2+积累；NDGA还可抑制Ca2+对谷氨酸的反应。NDGA可预防铁诱导的神经元损伤和ROS积累，表明NDGA作为抗氧化剂在其介导的神经保护中发挥作用。另一种脂氧合酶抑制剂（AA861）也可保护细胞免受Aβ和铁毒性的影响，而5-脂氧合酶激活蛋白抑制剂L655,238和环氧化酶抑制剂吲哚美辛则无效。这些发现表明，NDGA可中断与阿尔茨海默病病理生理学相关的神经退行性途径。
