BMAA selectively injures motor neurons via AMPA/kainate receptor activation
BMAA selectively injures motor neurons via AMPA/kainate receptor activation
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DOI：
10.1016/j.expneurol.2006.04.017
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发表时间：
2006-09-01
影响因子：
5.3
通讯作者：
Weiss, John H.
中科院分区：
文献类型：
--
作者：
Rao, Shyam D.;Banack, Sandra Anne;Weiss, John H.
毒素β -甲氨基- l -丙氨酸（BMAA）被认为是导致关岛肌萎缩性侧索硬化症-帕金森性痴呆复合物（ALS/PDC）的原因，这是基于它在灵长类动物中诱导类似疾病表型的能力，以及它在苏铁种子中的存在，而苏铁种子是受影响人群的一种饮食项目。由于担心这种毒素的效力明显低于人体摄入的估计水平，因此BMAA的研究放慢了速度。然而，最近的报告发现了潜在的新暴露途径，迫使人们重新审视BMAA/cycad假说。研究发现，BMAA在分离的混合脊髓培养物中诱导选择性运动神经元（MN）丢失的浓度（类似于30 μ M）明显低于先前发现的诱导广泛神经元变性的浓度。谷氨酸受体拮抗剂NBQX阻止bmaa诱导的死亡，暗示AMPA/kainate受体的兴奋毒性激活。利用微荧光技术，我们进一步发现BMAA诱导MNs中的优先[Ca2+](i)升高和选择性活性氧（ROS）产生，而对其他脊髓神经元的影响很小。苏铁种子提取物也会触发AMPA/kainate-receptor-dependent的优先MN损伤，这与BMAA是该植物的关键毒性成分的观点一致。目前的研究结果支持了BMAA可能导致ALS/PDC患者选择性MN损失的假设。(c) 2006爱思唯尔公司版权所有。
The toxin beta-methylamino-L-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations. Concerns about the apparent low potency of this toxin in relation to estimated levels of human ingestion led to a slowing of BMAA research. However, recent reports identifying potential new routes of exposure compel a re-examination of the BMAA/cycad hypothesis. BMAA was found to induce selective motor neuron (MN) loss in dissociated mixed spinal cord cultures at concentrations (similar to 30 mu M) significantly lower than those previously found to induce widespread neuronal degeneration. The glutamate receptor antagonist NBQX prevented BMAA-induced death, implicating excitotoxic activation of AMPA/kainate receptors. Using microfluorimetric techniques, we further found that BMAA induced preferential [Ca2+](i) rises and selective reactive oxygen species (ROS) generation in MNs with minimal effect on other spinal neurons. Cycad seed extracts also triggered preferential AMPA/kainate-receptor-dependent MN injury, consistent with the idea that BMAA is a crucial toxic component in this plant. Present findings support the hypothesis that BMAA may contribute to the selective MN loss in ALS/PDC. (c) 2006 Elsevier Inc. All rights reserved.