Peres Tanara Vieira, Pedro Daniela Zótico, de Cordova Fabiano Mendes, Lopes Mark William, Gonçalves Filipe Marques, Mendes-de-Aguiar Cláudia Beatriz Nedel, Walz Roger, Farina Marcelo, Aschner Michael, Leal Rodrigo Bainy
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, 88040-900 Florianópolis, SC, Brazil.
Biomed Res Int. 2013;2013:769295. doi: 10.1155/2013/769295. Epub 2013 Nov 13.
The molecular mechanisms mediating manganese (Mn)-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs) and tyrosine hydroxylase (TH) could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old). The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl₂; 10-1,000 μM) caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK) 1/2, as well as c-Jun N-terminal kinase (JNK) 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3) in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain.
介导锰（Mn）诱导的神经毒性的分子机制，尤其是在未成熟的中枢神经系统中的机制，尚未完全明确。在本研究中，我们调查了丝裂原活化蛋白激酶（MAPKs）和酪氨酸羟化酶（TH）是否可能是从14日龄未成熟大鼠获取的纹状体和海马体切片中锰的潜在作用靶点。本研究的目的是评估在亚毒性锰暴露后，MAPK通路是否受到调节，这种暴露不会显著影响细胞活力。在暴露3小时或6小时的切片中，氯化锰（MnCl₂；10 - 1000 μM）的浓度对细胞活力没有影响。然而，在两个脑区结构中，锰暴露在孵育3小时和6小时时均显著增加了细胞外信号调节激酶（ERK）1/2以及c - Jun氨基末端激酶（JNK）1/2/3的磷酸化。此外，锰暴露并未改变纹状体切片中TH在丝氨酸40位点的总含量或磷酸化水平。因此，在不破坏细胞活力的浓度下，锰会导致未成熟海马体和纹状体切片中MAPKs（ERK1/2和JNK1/2/3）的激活。这些发现表明，细胞内MAPKs信号通路的改变可能是锰对未成熟脑影响的早期事件。
