The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain.
The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain.
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DOI：
10.1016/j.tox.2011.11.017
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发表时间：
2012-02-26
期刊：
影响因子：
4.5
通讯作者：
Marreilha dos Santos, A. P.
中科院分区：
文献类型：
--
作者：
Santos, Dinamene;Milatovic, Dejan;Andrade, Vanda;Camila Batoreu, M.;Aschner, Michael;Marreilha dos Santos, A. P.
锰（Mn）是一种天然存在的元素，也是人类和动物的必需营养素。然而，暴露于高水平的锰可能会导致神经毒性作用。与锰神经毒性相关的病理机制尚不清楚，但一些报告已确定它至少部分由氧化应激介导。本研究进行了测试的假设，乙酰胆碱酯酶（AChE）活性的降低介导锰诱导的神经毒性。每组6只大鼠接受4或8只腹膜内（i. p.）注射25 mg MnCl 2/kg/天，每48小时一次。在最后一次注射后24小时，分析脑AChE活性和F2-异前列烷（F2-IsoPs）和F4-神经前列烷（F4-NPs）（氧化应激的生物标志物）以及前列腺素E2（PGE 2）（神经炎症的生物标志物）的水平。结果表明，在4或8个锰剂量后，脑AChE活性显著降低（p<0.05），分别为对照水平的60 ± 16%和55 ± 13%。两个给药组均表现出明显的神经行为毒性体征，其特征在于旷场中的勃起和勃起显著降低（p<0.001）。此外，Mn处理引起脑F2-IsoPs和PGE 2水平的显著增加（p<0.05），但仅在8次剂量后。为了评估细胞对氧化应激的反应，我们评估了脑核因子-红细胞2 p45相关因子2（Nrf 2）和锰超氧化物歧化酶（Mn-SOD，SOD 2）蛋白表达水平。与对照组相比，在4个Mn剂量后，在大鼠脑中注意到Mn-SOD蛋白表达的显著增加（p<0.05）和Nrf 2蛋白表达增加的趋势，但是在8个Mn剂量后，这些蛋白的表达降低。综上所述，这些结果表明，锰对乙酰胆碱酯酶活性的抑制作用促进了神经元氧化应激和神经炎症生物标志物的增加。
Manganese (Mn) is a naturally occurring element and an essential nutrient for humans and animals. However, exposure to high levels of Mn may cause neurotoxic effects. The pathological mechanisms associated with Mn neurotoxicity are poorly understood, but several reports have established it is mediated, at least in part, by oxidative stress. The present study was undertaken to test the hypothesis that a decrease in acetylcholinesterase (AChE) activity mediates Mn-induced neurotoxicity. Groups of 6 rats received 4 or 8 intraperitoneal (i.p.) injections of 25 mg MnCl2/kg/day, every 48 hours. Twenty-four hours after the last injection, brain AChE activity and the levels of F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs) (biomarkers of oxidative stress), as well as prostaglandin E2 (PGE2) (biomarker of neuroinflammation) were analyzed. The results showed that after either 4 or 8 Mn doses, brain AChE activity was significantly decreased (p<0.05), to 60 ± 16 % and 55 ± 13 % of control levels, respectively. Both treated groups exhibited clear signs of neurobehavioral toxicity, characterized by a significant (p<0.001) decrease in ambulation and rearings in open-field. Furthermore, Mn treatment caused a significant increase (p<0.05) in brain F2-IsoPs and PGE2 levels, but only after 8 doses. In rats treated with 4 Mn doses, a significant increase (p<0.05) in brain F4-NPs levels was found. To evaluate cellular responses to oxidative stress, we assessed brain nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Mn-superoxide dismutase (Mn-SOD, SOD2) protein expression levels. A significant increase in Mn-SOD protein expression (p<0.05) and a trend towards increased Nrf2 protein expression was noted in rat brains after 4 Mn doses vs. the control group, but the expression of these proteins was decreased after 8 Mn doses. Taken together, these results suggest that the inhibitory effect of Mn on AChE activity promotes increased neuronal oxidative stress and neuroinflammatory biomarkers.
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
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DOI：
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