Granulocyte-macrophage colony-stimulating factor promotes survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine Parkinson's disease model

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that has the potential for clinical application. The biological effects of GM-CSF have been well characterized, and include stimulation of bone marrow hematopoietic stem cell proliferation and inhibition of apoptosis of hematopoietic cells. In contrast, the therapeutic effects of GM-CSF on the central nervous system in acute injury such as stroke and spinal cord injury have been reported only recently. To better understand the protective effect of GM-CSF on dopaminergic neurons in Parkinson's disease (PD), we investigated the effect of GM-CSF on the survival of dopamine neurons and changes in locomotor behavior in a murine PD model. We investigated the neuroprotective effects of GM-CSF in 1-methyl-4-phenylpyridinium (MPP+)-treated PC12 cells as well as in embryonic mouse primary mesencephalic neurons (PMNs) in vitro. To investigate the role of GM-CSF in vivo, we prepared a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model, and examined the effects of GM-CSF on dopaminergic neuron survival in the substantia nigra and on locomotor behavior. Treatment with GM-CSF significantly reduced MPP+-induced dopaminergic cell death in PC12 cells and PMNs in vitro. GM-CSF modulated the expression of apoptosis-related proteins, Bcl-2 and Bax, in vitro. Furthermore, administration of GM-CSF (50 microg/kg body weight/day) in vivo for 7 days protected dopaminergic neurons in the substantia nigra and improved locomotor behavior in a mouse MPTP model of PD.