Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine in rodents
Bone morphogenetic protein-7 reduces toxicity induced by high doses of methamphetamine in rodents
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DOI：
10.1016/j.neuroscience.2007.10.044
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发表时间：
2008-01-02
期刊：
影响因子：
3.3
通讯作者：
Wang, Y.
中科院分区：
文献类型：
--
作者：
Chou, J.;Luo, Y.;Wang, Y.
甲基苯丙胺(MA)是一种滥用药物，也是一种多巴胺能神经毒素。我们先前已经证明，在帕金森病的啮齿动物模型中，骨形态发生蛋白7(BMP7)的预处理减少了6-羟基多巴胺介导的神经变性。在这项研究中，我们研究了BMP7对MA介导的多巴胺能神经元毒性的神经保护作用。从大鼠胚胎腹侧中脑组织中分离出原代多巴胺能神经元，用MA处理。大剂量MA可降低酪氨酸羟化酶免疫反应性，增加末端脱氧核苷酸转移酶介导的dNTP缺口末端标记。BMP7可显著拮抗这些毒性。首次在CD1小鼠体内研究了BMP7与MA的相互作用。高剂量MA(10 mg/kg x 4 s.c.)显著降低纹状体的运动活性和THIR。I.C.V.给予BMP7可拮抗这些变化。在BMP7+/-小鼠中，MA比野生型BMP7+/+小鼠更大程度地抑制黑质网状体内的运动活性和降低TH免疫反应性，这表明BMP7表达缺失增加了对MA侮辱的易感性。由于BMP7+/-小鼠在BMP7基因座上也携带LacZ表达的报告等位基因，因此通过测定BMP7+/-小鼠体内的β-半乳糖苷酶(β-GAL)活性来间接检测BMP7的表达。大剂量MA可显著抑制纹状体P-Gal活性，提示MA可能抑制黑质纹状体通路终末BMP7的表达。在CD1小鼠中也发现了类似的效应，高剂量的MA抑制了黑质BMP7mRNA的表达。综上所述，我们的数据表明，MA可以引起黑质纹状体多巴胺能终末的损害，BMP7对MA介导的中枢多巴胺能神经元的神经毒性具有保护作用。爱思唯尔有限公司代表伊布罗出版。
Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine-mediated neurodegeneration in a rodent model of Parkinson's disease. In this study, we examined the neuroprotective effects of BMP7 against MA-mediated toxicity in dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase immunoreactivity (THir) while increasing terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling. These toxicities were significantly antagonized by BMP7. Interaction of BMP7 and MA in vivo was first examined in CD1 mice. High doses of MA (10 mg/kg x 4 s.c.) significantly reduced locomotor activity and THir in striatum. I.c.v. administration of BMP7 antagonized these changes. In BMP7 +/- mice, MA suppressed locomotor activity and reduced TH immunoreactivity in nigra reticulata to a greater degree than in wild type BMP7 +/+ mice, suggesting that deficiency in BMP7 expression increases vulnerability to MA insults. Since BMP7 +/- mice also carry a LacZ-expressing reporter allele at the BMP7 locus, the expression of BMP7 was indirectly measured through the enzymatic activity of beta-galactosidase (beta-gal) in BMP7 +/- mice. High doses of MA significantly suppressed P-gal activity in striatum, suggesting that MA may inhibit BMP7 expression at the terminals of the nigrostriatal pathway. A similar effect was also found in CD1 mice in that high doses of MA suppressed BMP7 mRNA expression in nigra. In conclusion, our data indicate that MA can cause lesioning in the nigrostriatal dopaminergic terminals and that BMP7 is protective against MA-mediated neurotoxicity in central dopaminergic neurons. Published by Elsevier Ltd on behalf of IBRO.