Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons
Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons
复制标题
DOI：
10.1016/j.expneurol.2004.11.030
复制
发表时间：
2005-03-01
影响因子：
5.3
通讯作者：
Howells, DW
中科院分区：
文献类型：
--
作者：
Porritt, MJ;Batchelor, PE;Howells, DW
脑源性神经营养因子（BDNF）的表达在帕金森病实质中显著降低。黑鬼这种神经营养素对多巴胺能神经元存活具有有效影响，保护它们免受神经毒素MPTP和6-羟基多巴胺（6-RDA）的影响，这些神经毒素通常用于创建帕金森病的动物模型，并且还促进多巴胺能轴突发芽。在这项研究中，我们证明，反义寡核苷酸输注（200 nM，28天），以防止BDNF的生产在黑质的大鼠模仿许多功能的经典动物模型帕金森氏病。62%的反义治疗的大鼠旋转（P小于或等于0.05）响应多巴胺能受体的阿扑吗啡刺激。黑质背侧部酪氨酸羟化酶免疫反应阳性神经元丢失40%（P ≤ 0.00001），H-3-马吲哚放射自显影法测定的多巴胺摄取部位密度降低34%（P ≤ 0.005）。苏木精和伊红染色的黑质神经元的损失是显著的（P小于或等于0.0001），但不太广泛（34%）。这些观察结果表明，BDNF表达的损失导致多巴胺能表型的下调和多巴胺能神经元死亡。因此，帕金森病黑质中BDNF mRNA表达的减少可能直接导致黑质多巴胺能神经元的死亡和帕金森病的发展。(C)2004爱思唯尔公司All rights reserved.
Brain derived neurotrophic factor (BDNF) expression is significantly reduced in the Parkinson's disease substantia. nigra. This neurotrophin has potent affects on dopaminergic neuron survival protecting them from the neurotoxins MPTP and 6-hydroxydopamine (6-ORDA) commonly used to create animal models of Parkinson's disease and also promoting dopaminergic axonal sprouting. In this study, we demonstrate that an antisense oligonucleotide infusion (200 nM for 28 days) to prevent BDNF production in the substantia nigra of rats mimics many features of the classical animal models of Parkinson's disease. 62% of antisense treated rats rotate (P less than or equal to 0.05) in response to dopaminergic receptor stimulation by apomorphine. 40% of substantia nigra pars compacta tyrosine hydroxylase immunoreactive neurons are lost ( P less than or equal to 0.00001) and dopamine uptake site density measured by H-3-mazindol autoradiography is reduced by 34% (P less than or equal to 0.005). Loss of haematoxylin and eosin stained nigral neurons is significant (P less than or equal to 0.0001) but less extensive (34%). These observations indicate that loss of BDNF expression leads both to down regulation of the dopaminergic phenotype and to dopaminergic neuronal death. Therefore, reduced BDNF mRNA expression in Parkinson's disease substantia nigra may contribute directly to the death of nigral dopaminergic neurons and the development of Parkinson's disease. (C) 2004 Elsevier Inc. All rights reserved.