Erythropoietin as a Modulator of Pathology in a Toxicant Mouse Model of Parkinson’s Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and has no known disease-modifying treatments. Due to the complexity of the disease pathology, effective treatments for PD will likely involve a combination of treatment factors. The current experiments sought to profile the pro-survival effects of the trophic cytokine, erythropoietin (EPO), in a 6-hydroxydopamine (6-OHDA) mouse model of PD.Methods:To this end, male C57Bl/6 mice were used in a series of four experiments investigating the potential anti-apoptotic, anti-inflammatory and antioxidant effects of the trophic cytokine. EPO's ability to protect dopaminergic terminals in the striatum, cell bodies in the substantia nigra (SNc) and modulate 6-OHDA-induced motor deficits was characterized at different doses of 6-OHDA and EPO.Results:Our results did indeed demonstrate EPO's ability to exert pro-survival effects that were brain region-specific. While intra-nigral EPO was ineffective, intra-striatal EPO preserved striatal terminals and nigral soma in two different 6-OHDA lesion models. EPO further attenuated apomorphine-induced rotations at two doses of 6-OHDA. EPO demonstrated anti-apoptotic signalling through phosphorylation of Akt and the Bcl-2 associated proteins and anti-inflammatory activity through modulation of microglial morphology. Finally, EPO demonstrated antioxidant activity through elevated levels of striatal glutathione peroxidase, in addition to retrograde signalling that resulted in elevated levels of glutathione peroxidase in the SNc in response to EPO treatment.Conclusions:In short, EPO appears to modify antioxidant and anti-apoptotic factors and act in a brain-region specific manner to mitigate neuronal loss. Taken together, the results of the current set of experiments indicate EPO's potential for use as an adjuvant therapy in the treatment of PD.