G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway.
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-CSF. 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.
Huang
Hsin-Yi
HY
Neuro-Medical Scientific Center, Buddhist Tzu-Chi General Hospital, Tzu-Chi College of Technology, Hualien 970, Taiwan, ROC.
Lin
Shinn-Zong
SZ
Kuo
Jon-Son
JS
Chen
Wu-Fu
WF
Wang
Mei-Jen
MJ
D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000502:physiology
D018663:Adrenergic Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D016627:Oxidopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine