Granulocyte macrophage-colony stimulating factor protects against substantia nigra dopaminergic cell loss in an environmental toxin model of Parkinson's disease

Abstract

Parkinson's disease (PD) has been linked to exposure to a variety of chemical (e.g., pesticides) and inflammatory agents, which may act cumulatively over time. Finding novel means of limiting pathology associated with toxin exposure would have tremendous clinical importance. To this end, we assessed whether the hematopoietic trophic cytokine, granulocyte macrophage colony stimulating factor (GM-CSF), would inhibit the neurodegenerative effects of the pesticide, paraquat, administered either alone or following priming with the bacterial endotoxin, lipopolysaccharide (LPS). As previously observed, paraquat provoked a modest but significant neurodegenerative effect that was markedly augmented with LPS priming. Central infusion of GM-CSF into the substantia nigra pars compacta (SNc) prevented the loss of SNc dopamine neurons to a degree comparable to that of glial derived neurotrophic factor. Importantly, systemic administration of GM-CSF also had neuroprotective consequences, suggesting that the trophic cytokine can cross the blood brain barrier to promote neuronal survival. Indeed, GM-CSF acted to inhibit the LPS and paraquat induced microglial response, while augmenting astrocyte immunoreactivity within the SNc. Moreover, GM-CSF blunted the paraquat induced reduction of brain derived neurotrophic factor within the hippocampus, as well as in cultured mesencephalic neurons. Although paraquat reduced mesencephalic levels of the anti-apoptotic protein, Bcl-2, GM-CSF had no effect in this regard. Hence, GM-CSF appears to affect inflammatory and/or neuroplastic factors within the SNc that may be linked to neurodegeneration, as well as in other brain regions (hippocampus), which could be important for co-morbid non-motor symptoms in PD. These data suggest that peripheral GM-CSF administration might hold promise as a treatment of PD.