Rigon Ana Paula, Cordova Fabiano M, Oliveira Camila S, Posser Thaís, Costa Ana Paula, Silva Ilza G, Santos Daiane A, Rossi Francesco M, Rocha João Batista T, Leal Rodrigo B
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Neurotoxicology. 2008 Jul;29(4):727-34. doi: 10.1016/j.neuro.2008.04.017. Epub 2008 May 4.
The developing brain is very sensitive to damage by toxic agents, many of which only manifest in adulthood. Cadmium [Cd(II)] is an environmental pollutant which is widely used in industry and is a constituent of tobacco smoke. Exposure to Cd(II) has been linked to detrimental effects on mammalian cells including neural cells. We have investigated the action of Cd(II) on immature hippocampus by assessing cell viability and modulation of AKT/PKB and mitogen-activated protein kinase (MAPK) family members including extracellular signal-regulated kinase (ERK)-1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). Hippocampal slices from immature rats (postnatal day 14; PN14) were incubated with Cd(II) (5-200 microM) for 3h and the effects on protein phosphorylation were analyzed by western blotting. Phosphorylation of p38(MAPK) was enhanced by Cd(II) at all doses tested. Cd(II) also stimulated the phosphorylation of ERK1/2 in a concentration-dependent manner. However, the phosphorylation of JNK and AKT was not altered by the metal. Moreover, Cd(II) reduced cell viability, as measured by MTT reduction. Inhibition of p38 MAPK by SB203580 aggravated the acute Cd(II)-induced impairment of cell viability, whereas inhibition of MEK by PD98059 did not alter the effects of Cd(II). The present data suggest that in immature hippocampal cells p38 MAPK may be a part of signaling pathway that counteracts acute Cd(II) neurotoxicity. In conclusion, our results showed that Cd(II) impairs cell viability and disturbs MAPKs pathways in an important developmental stage for synaptic organization.
发育中的大脑对有毒物质的损害非常敏感，其中许多有毒物质仅在成年期才显现出来。镉[Cd(II)]是一种环境污染物，在工业中广泛使用，也是烟草烟雾的成分之一。接触Cd(II)与包括神经细胞在内的哺乳动物细胞的有害影响有关。我们通过评估细胞活力以及AKT/PKB和丝裂原活化蛋白激酶（MAPK）家族成员（包括细胞外信号调节激酶（ERK）-1/2、p38 MAPK和c-Jun氨基末端激酶（JNK））的调节作用，研究了Cd(II)对未成熟海马体的作用。将未成熟大鼠（出生后第14天；PN14）的海马体切片与Cd(II)（5-200 microM）孵育3小时，并通过蛋白质印迹法分析对蛋白质磷酸化的影响。在所有测试剂量下，Cd(II)均增强了p38(MAPK)的磷酸化。Cd(II)还以浓度依赖性方式刺激ERK1/2的磷酸化。然而，金属对JNK和AKT的磷酸化没有影响。此外，通过MTT还原法测定，Cd(II)降低了细胞活力。SB203580抑制p38 MAPK加重了急性Cd(II)诱导的细胞活力损伤，而PD98059抑制MEK并未改变Cd(II)的作用。目前的数据表明，在未成熟的海马体细胞中，p38 MAPK可能是对抗急性Cd(II)神经毒性的信号通路的一部分。总之，我们的结果表明，Cd(II)在突触组织的一个重要发育阶段损害细胞活力并扰乱MAPKs通路。
