毕赤酵母表达的neurturin对恒河猴帕金森氏病模型中黑质多巴胺能神经元的保护作用
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云南省自然科学基金资助项目(2003C0026Q).


Protection of Dopaminergic Neurons by Recombinant Neurturin Secreted From Pichia pastoris in a Rhesus Monkey Model of Parkinson's Disease
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This work was supported by a grant from The Yunnan Natural Science Foundation(2003C0026Q).

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    摘要:

    帕金森氏病(PD)是由于多巴胺能神经元变性、坏死,导致黑质-纹状体系统的多巴胺含量下降而引起的一种神经系统退行性疾病,目前还没有一种很好的方法能使之治愈.Neurturin(NTN)能特异地作用于中脑多巴胺能神经元,对该类神经元具营养和保护作用.经静脉注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导恒河猴产生帕金森氏病模型,并在NTN治疗组,注射MPTP之前48 h脑室内注射重组毕赤酵母表达的人NTN 1 mg. 结果表明:模型组猴均逐渐出现了PD症状,而NTN治疗组猴,PD症状比较轻或不明显;荧光分光光度法测定MPTP模型组猴黑质、壳核和尾状核多巴胺(DA)、5-羟色胺(5-HT)和5-羟吲哚乙酸(5-HIAA)的含量结果与正常对照组相比均显著降低,NTN治疗组猴的黑质、壳核和尾状核中的DA、5-HT和5-HIAA与对照组相比无显著性差异,而与模型组相比,DA、5-HT和5-HIAA含量均明显增加;光镜检查MPTP模型组猴黑质神经元细胞明显脱失,而NTN治疗组猴黑质神经元细胞丢失不明显,与正常对照组猴无差别.上述结果表明,制备的重组人NTN在恒河猴体内能保护中脑黑质多巴胺能神经元不受MPTP的损伤,使其DA含量及多巴胺能神经元维持正常,在MPTP存在下没有发生PD症状.

    Abstract:

    Parkinson's disease (PD) is a neurodegenerative disease due to lack of dopamine (DA) in nigrostriatal system resulting from the degeneration and necrosis of dopaminergic neurons. No effective cure has been found. Neurturin (NTN) has been demonstrated to protect mesencephalic dopaminergic neurons specifically. Parkinson's disease was induced in rhesus monkeys by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). Rhesus monkeys were randomly divided into a PD model, NTN treatment and normal control groups. In the NTN treatment group, 1 mg of Pichia pastoris -derived recombinant human NTN was injected into the cerebral ventricles 48 h prior to injection of MPTP. Rhesus monkeys in the PD model group acquired PD symptoms that progressed over time, while monkeys treated with NTN had less apparent or no symptoms. Using fluorospectrophotometry, the dopamine (DA), 5-hydroxytry-ptamine (5-HT) and the 5-hydroxyindoleacetic acid (5-HIAA) in substantia nigra, putamen and caudate nucleus in monkeys from the model group were found to be significantly lower than in the normal control group. No significant differences were found between the NTN treatment and normal control groups, but the contents of DA, 5-HT and 5-HIAA in the NTN treatment group were higher than those observed in the PD model group. A dramatic loss of neurons in the substantia nigra in monkeys in the PD model group was observed by light microscopy, while no obvious loss was observed in the NTN treatment group in which the numbers of neurons were similar to those in normal controls. These results indicate that Pichia pastoris -derived recombinant human NTN can prevent PD symptoms as well as protect dopaminergic neurons and preserve DA content in midbrain substantia nigra in rhesus monkeys exposed to MPTP.

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李鸿钧,苏婷,马雁冰,和占龙,鲁帅尧,戴长柏,孙茂盛.毕赤酵母表达的neurturin对恒河猴帕金森氏病模型中黑质多巴胺能神经元的保护作用[J].生物化学与生物物理进展,2004,31(8):722-726

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  • 收稿日期:2004-02-05
  • 最后修改日期:2004-03-30
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