Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease
Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease
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DOI：
10.1111/j.1471-4159.2006.03727.x
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发表时间：
2006-05-01
影响因子：
4.7
通讯作者：
Weishaupt, JH
中科院分区：
文献类型：
--
作者：
Meuer, K;Pitzer, C;Weishaupt, JH
我们最近表明，造血粒细胞集落刺激因子（G-CSF）在啮齿动物中风模型中具有神经保护作用，并且这种作用似乎是通过神经元G-CSF受体介导的。在这里，我们报告说，G-CSF受体表达在啮齿动物黑质多巴胺能神经元，表明G-CSF可能是多巴胺能神经元的神经保护和帕金森病的治疗的候选分子。因此，我们研究了G-CSF在1-甲基-4-苯基吡啶（MPP+）攻击的PC 12细胞和原代神经元中脑培养物中的保护作用，以及在帕金森病的小鼠1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）模型中的保护作用。在体外发现了对MPP+诱导的多巴胺能细胞死亡的实质性保护。此外，如酪氨酸羟化酶阳性黑质细胞的定量所示，在13天内每天以40 μ g/Kg体重的剂量皮下应用G-CSF从MPTP诱导的老年小鼠死亡中拯救多巴胺能黑质神经元。使用HPLC，在G-CSF处理的小鼠中观察到MPTP应用后纹状体多巴胺消耗的相应减少。因此，我们的数据表明，G-CSF是治疗帕金森病的一种新的治疗机会，因为它是耐受性良好的，并已被批准用于治疗人类的血小板减少症。
We have recently shown that the hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) is neuroprotective in rodent stroke models, and that this action appears to be mediated via a neuronal G-CSF receptor. Here, we report that the G-CSF receptor is expressed in rodent dopaminergic substantia nigra neurons, suggesting that G-CSF might be neuroprotective for dopaminergic neurons and a candidate molecule for the treatment of Parkinson's disease. Thus, we investigated protective effects of G-CSF in 1-methyl-4-phenylpyridinium (MPP+)-challenged PC12 cells and primary neuronal midbrain cultures, as well as in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Substantial protection was found against MPP+-induced dopaminergic cell death in vitro. Moreover, subcutaneous application of G-CSF at a dose of 40 mu g/Kg body weight daily over 13 days rescued dopaminergic substantia nigra neurons from MPTP-induced death in aged mice, as shown by quantification of tyrosine hydroxylase-positive substantia nigra cells. Using HPLC, a corresponding reduction in striatal dopamine depletion after MPTP application was observed in G-CSF-treated mice. Thus our data suggest that G-CSF is a novel therapeutic opportunity for the treatment of Parkinson's disease, because it is well-tolerated and already approved for the treatment of neutropenic conditions in humans.