Recombinant human granulocyte colony‐stimulating factor protects against MPTP‐induced dopaminergic cell death in mice by altering Bcl‐2/Bax expression levels

Abstract

Granulocyte colony-stimulating factor (G-CSF) has been used for the treatment of neutropenia in hematologic disorders. The neuroprotective effects of G-CSF were reported in neurological disease models. In the present study, we examined whether G-CSF can protect dopaminergic neurons against MPTP-induced cell death in a mouse model of Parkinson's disease. Mice of one group were injected intraperitoneally with MPTP for five consecutive days, those of another group with MPTP and intraperitoneal G-CSF at 2 days and 1 day before the first MPTP injection, and 30 min before each MPTP injection, while control mice received saline injections. Immunohistochemistry, western blotting analysis, and HPLC were performed to evaluate damage of substantia nigra dopaminergic neurons and expression of Bcl-2 and Bax protein. MPTP induced dopaminergic cell death in the substantia nigra. G-CSF significantly prevented MPTP-induced loss of tyrosine hydroxylasepositive neurons (p < 0.05), increased Bcl-2 protein and decreased Bax protein expression. Our findings indicate that G-CSF provides neuroprotection against MPTP-induced cell death and this effect is mediated by increasing Bcl-2 expression levels and decreasing Bax expression levels in C57BL/6 mice.

The Role of Granulocyte-Colony Stimulating Factor (G-CSF) in the Healthy Brain: A Characterization of G-CSF-Deficient Mice

“…Numerous reports have described the efficacy of G-CSF in animal models of different neurological diseases including stroke (Schabitz et al, 2003;Schneider et al, 2005;KomineKobayashi et al, 2006;Solaroglu et al, 2006;Minnerup et al, 2008), Parkinson's disease (Cao et al, 2006;Meuer et al, 2006), and Alzheimer's disease (Tsai et al, 2007). These studies confirm G-CSF as a neurotrophic factor, and ascertained its role in neuroprotection and neuroregeneration relevant to the most prominent neurodegenerative diseases.…”

Control of Cell Survival in Adult Mammalian Neurogenesis

“…Trophic factors, such as fibroblast growth factor (FGF)-2, brain-derived neurotrophic factor (BDNF), granulocyte colony-stimulating factor (G-CSF), and vascular endothelial growth factor (VEGF), can directly stimulate expression of antiapoptotic Bcl-2 family proteins (Fig. 2) (Bryckaert et al 1999;Desire et al 2000;RiosMunoz et al 2005;Cao et al 2006;Solaroglu et al 2006;Milosevic et al 2007), thereby counteracting Bax and Bak functions and preventing caspase activation.…”

Post-MPTP Treatment with Granulocyte Colony-Stimulating Factor Improves Nigrostriatal Function in the Mouse Model of Parkinson’s Disease

“…In order to investigate whether G-CSF has a neuroregenerative effect, it is important verify that the degeneration of dopaminergic neurons is complete before G-CSF intervention to properly differentiate from the neuroprotective effect as reported [7,8]. Therefore, we first generated the MPTP mice and examined the time-dependent degeneration of dopaminergic neurons.…”

“…Increasing evidence from recent studies indicates that G-CSF is neuroprotective in vivo and in vitro [3,5,6]. For example, G-CSF protects against neurodegeneration in a number of neurological disease models such as PD [7,8], Huntington's disease [9], and cerebral ischemia [10,11].…”