Lin Anya M Y, Fang S F, Chao P L, Yang C H
Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
J Pineal Res. 2007 Sep;43(2):163-71. doi: 10.1111/j.1600-079X.2007.00456.x.
In the present study, the protective effect of melatonin on sodium arsenite (arsenite)-induced apoptosis was investigated. Local infusion of arsenite elevated lipid peroxidation and depleted glutathione content in the infused substantia nigra (SN), as well as reduced striatal dopamine content. Systemic administration of melatonin diminished arsenite-induced oxidative injury. Furthermore, melatonin attenuated arsenite-induced increases in heat shock protein 70 and heme oxygenase-1 as well as phosphorylation of p38 mitogen-activated protein kinase and elevations in cyclooxygenase II and inducible nitric oxide synthase expression. Inhibition by melatonin of arsenite-induced apoptosis was determined by its attenuation of DNA fragmentation and terminal deoxytransferase-mediated dUTP-nick end labeling's positive cells in the infused SN of melatonin-treated rats. Melatonin reduced arsenite-induced apoptosis through mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, systemic melatonin inhibited arsenite-induced elevations in Bcl-2 and cytosolic cytochrome c as well as arsenite-induced reductions in procaspase-3 levels and elevations in active caspase-3 levels in the infused SN. Regarding the ER pathway, melatonin attenuated arsenite-induced elevations in activating transcription factor-4, CCAAT/enhancer binding protein (C/EBP) homologues protein, X-bon binding protein (XBP-1) and cytosolic immunoglobulin binding protein (BIP) as well as reductions in procaspase 12 levels. Moreover, aggregation of alpha-synuclein was reduced in the arsenite-infused SN of melatonin-treated rats. Our in vitro data showed that melatonin ameliorated arsenite-induced lipid peroxidation. Taken together, our data suggest that melatonin is neuroprotective against arsenite-induced oxidative injury in the nigrostriatal dopaminergic system of rat brain. Furthermore, the neuroprotective effects by melatonin on arsenite-induced apoptosis were mediated via inhibiting both mitochondrial and ER pathways. Accordingly, melatonin may be therapeutically useful for the treatment of arsenite-induced apoptosis in central nervous system.
在本研究中，研究了褪黑素对亚砷酸钠（砷酸盐）诱导的细胞凋亡的保护作用。局部注入砷酸盐会升高脂质过氧化水平，降低注入的黑质（SN）中的谷胱甘肽含量，并降低纹状体多巴胺含量。全身给予褪黑素可减轻砷酸盐诱导的氧化损伤。此外，褪黑素可减弱砷酸盐诱导的热休克蛋白70和血红素加氧酶-1的增加，以及p38丝裂原活化蛋白激酶的磷酸化，以及环氧合酶II和诱导型一氧化氮合酶表达的升高。通过褪黑素处理的大鼠注入的SN中DNA片段化的减弱以及末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞的减少，确定了褪黑素对砷酸盐诱导的细胞凋亡的抑制作用。褪黑素通过线粒体和内质网（ER）途径减少砷酸盐诱导的细胞凋亡。在线粒体途径中，全身给予褪黑素可抑制砷酸盐诱导的注入的SN中Bcl-2和细胞色素c的升高，以及砷酸盐诱导的procaspase-3水平的降低和活性caspase-3水平的升高。关于ER途径，褪黑素减弱了砷酸盐诱导的激活转录因子-4、CCAAT/增强子结合蛋白（C/EBP）同源蛋白、X盒结合蛋白（XBP-1）和细胞溶质免疫球蛋白结合蛋白（BIP）的升高，以及procaspase 12水平的降低。此外，在褪黑素处理的大鼠注入砷酸盐的SN中，α-突触核蛋白的聚集减少。我们的体外数据表明，褪黑素可改善砷酸盐诱导的脂质过氧化。综上所述，我们的数据表明，褪黑素对大鼠脑黑质纹状体多巴胺能系统中砷酸盐诱导的氧化损伤具有神经保护作用。此外，褪黑素对砷酸盐诱导的细胞凋亡的神经保护作用是通过抑制线粒体和ER途径介导的。因此，褪黑素可能在治疗砷酸盐诱导的中枢神经系统细胞凋亡方面具有治疗作用。
