Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.
Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.
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DOI：
10.1007/s00204-013-1017-5
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发表时间：
2013-07
影响因子：
6.1
通讯作者：
Leal RB
中科院分区：
文献类型：
--
作者：
Cordova FM;Aguiar AS Jr;Peres TV;Lopes MW;Gonçalves FM;Pedro DZ;Lopes SC;Pilati C;Prediger RD;Farina M;Erikson KM;Aschner M;Leal RB
虽然锰对中枢神经系统(CNS)的正常发育是必不可少的，但过量的锰暴露可能会导致神经毒性。MN优先聚集在基底节，在成人中可能导致帕金森氏病(PD)样疾病。与成年个体相比，年轻个体在中枢神经系统积累了更多的锰水平，更容易受到其毒性的影响。此外，介导发育期锰诱导的神经毒性的机制还不完全清楚。本研究探讨了锰暴露(5、10和20 mg/kg；I.P.)所引起的发育神经毒性。从出生后第8天(PN8)到PN27。对PN29进行了神经化学分析，特别关注纹状体细胞内信号通路(MAPKs、AKT和DARPP-32)的变化、氧化应激的产生和细胞死亡。在3周龄、4周龄和5周龄时，在以后的生活中对运动改变进行评估。锰暴露(20 mg/kg)可增加p38MAPK和AKT的磷酸化，但降低DARPP-32-Thr-34的磷酸化。锰(10 mg/kg和20 mg/kg)增加了caspase活性和F2-异丙烷(脂质过氧化的生物标志)的产生。与纹状体生化参数的变化类似，锰(20 mg/kg)也引起运动障碍，表现为旋转杆试验中跌倒潜伏期的延长，以及开场试验中行走距离和速度的减少。值得注意的是，抗氧化剂Trolox™逆转了锰(20 mg/kg)对p38MAPK磷酸化的依赖增强，并降低了锰(20 mg/kg)诱导的半胱氨酸氨基转移酶活性和F2-异丙烷的产生。Trolox™还逆转了锰诱导的运动协调缺陷。这些发现首次表明，在神经发育的关键时期长期暴露于锰可以激活纹状体p38MAPK信号通路和caspase活性，并通过可能由活性氧(ROS)介导的机制导致运动协调功能障碍。
While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia and in adults it may cause Parkinson’s disease (PD)-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS, and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, AKT and DARPP-32), production of oxidative stress and cell death. Motor alterations were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn exposure (20 mg/kg) increased p38MAPK and AKT phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F2-isoprostrane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, and decreased distance travelled and the speed in the open-field test. Notably, the antioxidant Trolox™ reversed the Mn (20 mg/kg)-dependent augmentation in p38MAPK phosphorylation, and reduced the Mn (20 mg/kg)-induced caspase activity and F2-isoprostrane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment activates the striatal p38MAPK signaling pathway and caspase activity, and causes motor coordination dysfunction by a mechanism that is likely mediated by reactive oxygen species (ROS).
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影响因子：
3.7
作者：
Fitsanakis VA;Zhang N;Garcia S;Aschner M
通讯作者：
Aschner M
影响因子：
3.4
作者：
Avila, Daiana Silva;Gubert, Priscila;Antunes Soares, Felix Alexandre
通讯作者：
Antunes Soares, Felix Alexandre
DOI：
10.1196/annals.1306.009
发表时间：
2004-01-01
期刊：
REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS
影响因子：
--
作者：
Dobson, AW;Erikson, KM;Aschner, M
通讯作者：
Aschner, M
影响因子：
3.7
作者：
Cordova FM;Aguiar AS Jr;Peres TV;Lopes MW;Gonçalves FM;Remor AP;Lopes SC;Pilati C;Latini AS;Prediger RD;Erikson KM;Aschner M;Leal RB
通讯作者：
Leal RB
影响因子：
168.9
作者：
Fell, JME;Reynolds, AP;Milla, PJ
通讯作者：
Milla, PJ