Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536 , USA.
Environ Health Perspect. 2010 May;118(5):627-34. doi: 10.1289/ehp.0901510.
Arsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders.
We evaluated the role of the LKB1-AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a model of developing neurons.
The addition of low concentrations of As (<or= 5 microM) during differentiation caused an inhibitory effect on the neurite outgrowth in N2a cells in the absence of cell death. Activation of adenosine monophosphate-activated kinase (AMPK) induced by retinoic acid in differentiating cells was blocked by As. Pretreatment with the AMPK-specific activator 5-aminoimidazole-4-carboxamide riboside or overexpression of a constitutively active AMPK-alpha1 plasmid reversed As-induced inhibition of neurite outgrowth. The activation of LKB1 (serine/threonine kinase 11), a major AMPK kinase, was also suppressed by As by inhibiting both the phosphorylation and the translocation of LKB1 from nucleus to cytoplasm. Antioxidants, such as N-acetyl cysteine and superoxide dismutase, but not catalase, protected against As-induced inactivation of the LKB1-AMPK pathway and reversed the inhibitory effect of As on neurite outgrowth.
Reduced neurite outgrowth induced by As results from deficient activation of AMPK as a consequence of a lack of activation of LKB1. Oxidative stress induced by As, especially excessive superoxide, plays a critical role in blocking the LKB1-AMPK pathway. Our studies provide insight into the mechanisms underlying As-induced developmental neurotoxicity, which is important for designing a new strategy for protecting children against this neurotoxic substance.
砷（As）是一种环境污染物，可引起多种病理效应，包括神经发育障碍。
我们使用神经母细胞瘤（N2a）细胞作为发育神经元的模型，评估 LKB1-AMPK 通路在 As 诱导的发育神经毒性中的作用。
在分化过程中添加低浓度的 As（<或=5μM）会在没有细胞死亡的情况下抑制 N2a 细胞的突起生长。As 阻断了维甲酸诱导的分化细胞中腺苷单磷酸激活蛋白激酶（AMPK）的激活。用 AMPK 特异性激活剂 5-氨基咪唑-4-甲酰胺核苷或过表达组成型激活的 AMPK-α1 质粒预处理可逆转 As 诱导的突起生长抑制。LKB1（丝氨酸/苏氨酸激酶 11）的激活也被 As 抑制，这抑制了 LKB1 的磷酸化和从核到细胞质的易位，从而抑制了 LKB1。抗氧化剂，如 N-乙酰半胱氨酸和超氧化物歧化酶，但不是过氧化氢酶，可防止 As 诱导的 LKB1-AMPK 通路失活，并逆转 As 对突起生长的抑制作用。
As 诱导的突起生长减少是由于 AMPK 激活不足，这是由于 LKB1 缺乏激活所致。As 诱导的氧化应激，特别是过量的超氧自由基，在阻断 LKB1-AMPK 通路中起关键作用。我们的研究为 As 诱导的发育神经毒性的机制提供了深入的了解，这对于设计保护儿童免受这种神经毒性物质侵害的新策略非常重要。
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