파킨슨 동물모델에서의 GM-CSF가 도파민 신경세포의 생존과 운동능력에 미치는 영향

초록

PURPOSE : Granulocyte macrophage–colony stimulating factor (GM-CSF) is a hematopoietic cytokine which can be approved for clinical application. However, its therapeutic effects in the central nervous system have only been revealed recently. We investigated whether the GM-CSF can protect dopaminergic neuron in Parkinson’s disease (PD) model. MATERIALS AND METHODS : PC12 cells and embryonic mouse primary mesencephalic neurons (PMNs) culture with or without GM-CSF pre-treatment were treated with 1-methyl-4- phenylpyridinium (MPP+) in culture. And mitochondrial fraction of PC12 cell was prepared for monitoring complex Ⅰ activity. Mitochondrial membrane potential and ROS were measured. We also prepared a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse PD model, and GM-CSF was administrated daily for consecutive 7 days. Quantification of tyrosine hydroxylase (TH)-positive cells was performed to evaluate the damage of substantia nigra. And we carried out the open field test in the animal models. RESULTS : GM-CSF showed protective effect on doparminergic neurons both in vitro and in vivo. GM-CSF significantly reduced MPP+ induced dopaminergic cell death in PC12 cells and PMNs culture and mitochondrial dysfunction in PC12 cell. Furthermore, the administration of GM-CSF protected dopaminergic neurons from cell death. In addition, GM-CSF improved locomotor behavior and rescued dopaminergic level in mouse PD model. CONCLUSION : GM-CSF shows neuroprotective effect in our experimental PD model, but the underlying mechanisms remains largely unresolved. GM-CSF has been proved safe for hematologic patients, while considering GM-CSF as a clinical therapeutic agent for PD patients. We also need to study more for resolving safety in treatment of neural diseases such as Parkinson’s disease.