G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway
G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway
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DOI：
10.1016/j.neurobiolaging.2006.05.037
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Wang, Mei-Jen
中科院分区：
文献类型：
--
作者：
Huang, Hsin-Yi;Lin, Shinn-Zong;Wang, Mei-Jen
粒细胞集落刺激因子（G-CSF）具有诱导造血细胞存活、增殖和分化等多种功能。近年来，该因子在大鼠缺血脑中也显示出神经保护作用。在本研究中，我们首次证实了G-CSF和G-CSF受体在成人黑质和中脑培养的多巴胺能神经元中均有表达，提示G-CSF可能在多巴胺能神经元中发挥神经保护作用。G-CSF预处理可保护多巴胺能神经元免受6-羟基多巴胺（6-OHDA）诱导的神经毒性。对潜在机制的研究表明，在G-CSF处理后，细胞外调节激酶（ERK）被激活，而非Janus激酶/信号换能器和转录激活器（JAK/STAT）被激活。此外，G-CSF还增加Bad的磷酸化，恢复6- ohda诱导的Bcl-xL水平下降。G-CSE可抑制6- ohda引起的多巴胺能神经元中caspase-3的激活。抑制ERK可使g - csf介导的Bad磷酸化、Bcl-xL表达、激活caspase-3的还原以及对多巴胺能神经元的保护作用消失。综上所述，G-CSF通过ERK途径阻止多巴胺能神经元发生6-羟多巴胺诱导的毒性，随后抑制凋亡-执行过程。这些结果提示G-CSF可能在帕金森病中具有治疗潜力。(c) 2006爱思唯尔公司版权所有。
Granulocyte colony-stimulating factor (G-CSF) is known to have various functions such as induction of survival, proliferation and differentiation of hematopoietic cells. Recently, this factor has also been shown to exhibit neuroprotective effects in rat ischemic brain. In the present study, we first demonstrated that both G-CSF and G-CSF receptor were expressed in dopaminergic neurons in the adult substantia nigra and mesencephalic cultures, suggesting that G-CSF might exert its neuroprotective effects in dopaminergic neurons. Pretreatment with G-CSF protected dopaminergic neurons from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Investigation of the underlying mechanisms showed that the extracellular-regulated kinase (ERK), but not Janus kinase/signal transducer(s) and activator(s) of transcription (JAK/STAT), was activated following G-CSF treatment. Moreover, G-CSF also increased phosphorylation of Bad, and restored 6-OHDA-induced decrease in Bcl-xL level. The 6-OHDA-caused caspase-3 activation in dopaminergic neurons was inhibited by G-CSE Inhibition of ERK abrogated G-CSF-mediated Bad phosphorylation, Bcl-xL expression, activated caspase-3 reduction, and the protection of dopaminergic neurons. Taken together, G-CSF prevents dopaminergic neurons from 6-OHDA-induced toxicity via ERK pathway followed by inhibiting the apoptosis-execution process. These results suggest that G-CSF might have a therapeutic potential in Parkinson's disease. (c) 2006 Elsevier Inc. All rights reserved.