Zhang Ping, Hatter Angela, Liu Bin
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
Toxicol Lett. 2007 Sep 10;173(2):88-100. doi: 10.1016/j.toxlet.2007.06.013. Epub 2007 Jun 28.
Elevated exposure to manganese is known to cause neurodegeneration in the basal ganglia and to induce movement abnormalities called manganism. However, the underlying mechanism of action is not fully understood. Activation of the resident immune cells in the brain, microglia that release a variety of neurotoxic factors, has been implicated to contribute to neurodegeneration. Of the various neurotoxic factors released by activated microglia, reactive oxygen species such as superoxide and hydrogen peroxide are particularly detrimental to the survival of the oxidative damage-prone neurons. In this study, we report that exposure of rat microglia to manganese chloride (MnCl(2)) resulted in a time- and concentration-dependent release of hydrogen peroxide (H(2)O(2)). The MnCl(2)-stimulated microglial H(2)O(2) release was sensitive to inhibitors of mitogen-activated protein kinases (MAPK) but not that of NADPH oxidase. MnCl(2)-induced a rapid activation of the extracellular signal-regulated kinase (ERK) and p38-MAPK in microglia that appeared to precede the MnCl(2)-induced H(2)O(2) release, suggesting that ERK and p38-MAPK influenced the MnCl(2)-induced H(2)O(2) release in microglia. In summary, these results demonstrate that manganese chloride is capable of activating microglia to release ROS and MAPK may, in part, be key regulators of the process. These findings may shed significant light on the potential role of microglia in the manganese-induced neurotoxicity.
已知接触过量锰会导致基底神经节神经退行性变，并引发称为锰中毒的运动异常。然而，其潜在作用机制尚未完全明确。大脑中的常驻免疫细胞——小胶质细胞被激活后会释放多种神经毒性因子，这被认为与神经退行性变有关。在激活的小胶质细胞释放的各种神经毒性因子中，超氧化物和过氧化氢等活性氧对易受氧化损伤的神经元存活特别有害。在本研究中，我们报告大鼠小胶质细胞暴露于氯化锰（MnCl₂）会导致过氧化氢（H₂O₂）呈时间和浓度依赖性释放。MnCl₂刺激的小胶质细胞H₂O₂释放对丝裂原活化蛋白激酶（MAPK）抑制剂敏感，但对NADPH氧化酶抑制剂不敏感。MnCl₂诱导小胶质细胞中的细胞外信号调节激酶（ERK）和p38-MAPK快速激活，这似乎先于MnCl₂诱导的H₂O₂释放，表明ERK和p38-MAPK影响了MnCl₂诱导的小胶质细胞H₂O₂释放。总之，这些结果表明氯化锰能够激活小胶质细胞释放ROS，MAPK可能部分是该过程的关键调节因子。这些发现可能为小胶质细胞在锰诱导的神经毒性中的潜在作用提供重要线索。
