Potent neuroprotective properties against the Alzheimer β-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid
Potent neuroprotective properties against the Alzheimer β-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid
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DOI：
10.1074/jbc.274.31.21937
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发表时间：
1999-07-30
影响因子：
4.8
通讯作者：
Pappolla, MA
中科院分区：
文献类型：
--
作者：
Chyan, YJ;Poeggeler, B;Pappolla, MA
广泛的大脑沉积的40-43个氨基酸的肽称为淀粉样β蛋白（A β）的淀粉样纤维的形式是阿尔茨海默病的最突出的神经病理学特征之一。大量研究表明A β通过自由基介导的机制对神经元具有毒性，我们先前已经报道褪黑激素防止暴露于A β的神经元的氧化应激和死亡，在筛选吲哚化合物对A β的神经保护的过程中，发现了内源性相关物质吲哚-3-丙酸（IPA）的有效神经保护特性，这种化合物以前曾在人类的血浆和脑脊液中被鉴定，但其功能尚不清楚。IPA完全保护原代神经元和神经母细胞瘤细胞免受由暴露于A β、通过抑制超氧化物歧化酶或通过用过氧化氢处理引起的氧化损伤酸死亡。在使用自由基捕获剂的动力学竞争实验中，IPA清除羟基自由基的能力超过了褪黑激素，褪黑激素是一种吲哚胺，被认为是最有效的天然存在的自由基清除剂。与其他抗氧化剂相比，IPA没有转化为具有促氧化活性的活性中间体。这些发现可能在广泛的临床情况下具有治疗应用。
Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid beta-protein (A beta) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that A beta is toxic to neurons by free radical-mediated mechanisms, We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to A beta, In the process of screening indole compounds for neuroprotection against A beta, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA), This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage acid death caused by exposure to A beta, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide, In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.