In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function.
In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function.
复制标题
DOI：
10.1371/journal.pone.0033057
复制
发表时间：
2012
期刊：
影响因子：
3.7
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;Remor AP;Lopes SC;Pilati C;Latini AS;Prediger RD;Erikson KM;Aschner M;Leal RB
锰（Mn）是发育和新陈代谢所必需的金属。然而，暴露于高锰水平可能是有毒的，特别是对中枢神经系统（CNS）。神经毒性通常是由于职业或环境暴露，导致基底神经节中的锰蓄积和帕金森样疾病。年轻人更容易受到锰中毒的影响。此外，早期暴露可能是日后发生神经退行性疾病的风险因素。本研究旨在研究暴露于Mn（5、10和20 mg/kg; i.p.）的未成年大鼠体内模型中的发育神经毒性。从出生后第8天（PN8）至PN12。对PN14进行神经化学分析。我们专注于纹状体细胞内信号通路的改变，氧化应激和细胞死亡。此外，运动改变作为早期锰暴露（PN8 - 12）的结果进行了评估，在以后的生活在3，4和5周龄。锰以剂量依赖性方式改变了关键细胞信号传导元件的活性。具体地，Mn增加DARPP-32-Thr-34、ERK 1/2和AKT的磷酸化。此外，锰增加活性氧（ROS）的生产和半胱天冬酶的活性，并改变线粒体呼吸链复合物I和II的活动。锰（10和20毫克/公斤）也损害运动协调在第3，第4和第5周的生活。抗氧化剂Trolox ™逆转了Mn改变的几个参数，包括增加的ROS产生和ERK 1/2磷酸化。然而，Trolox ™未能逆转Mn（20 mg/kg）诱导的AKT磷酸化和运动缺陷的增加。此外，Mn（20 mg/kg）在旷场试验中降低了距离、速度和梳理频率; Trolox ™仅阻断梳理频率的降低。总之，这些结果表明，短期暴露于锰在特定的发育窗口（PN8 - 12）诱导代谢和神经化学的纹状体的变化，可能会调节晚年的行为变化。此外，一些分子和行为的事件，这是由早期锰暴露的干扰没有直接关系到氧化应激的生产。
Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn altered in a dose-dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3rd, 4th and 5th week of life. Trolox™, an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, Trolox™ failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; Trolox™ blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress.
登录
查看更多内容
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
影响因子：
8.2
作者：
Borgkvist, Anders;Fisone, Gilberto
通讯作者：
Fisone, Gilberto
影响因子：
4.8
作者：
Barros, MH;Bandy, B;Kowaltowski, AJ
通讯作者：
Kowaltowski, AJ
影响因子：
64.8
作者：
Chang, LF;Karin, M
通讯作者：
Karin, M
影响因子：
4.5
作者：
Bagh, Maria Bindu;Thakurta, Ishita Guha;Chakrabarti, Sasanka
通讯作者：
Chakrabarti, Sasanka