Erythropoietin as a neuroprotective molecule in Parkinson’s Disease: a focus on mitochondrial metabolism

Existing therapies for Parkinson's disease (PD) are only symptomatic and there is thus a need to identify novel therapeutic strategies for the disease. The role of Erythropoietin (EPO) as possible drug for the treatment of Parkinson’s Disease (PD) is gaining more and more relevance, and in this study, we focused on the neuroprotective role of recombinant human EPO (rhEPO) in both in vitro and in vivo models of the disease. SH-SY5Y cells were treated with 500 microM MPP+ for 24 hours. Cell viability was assessed via MTT assay, and an assessment of dopaminergic recovery was performed via Real Time PCR, Western Blot and Immunofluorescence. Moreover, mitochondrial health was investigated via Mitotracker staining, Transmission Electron Microscopy and seahorse analysis. As in vivo model of PD, C5BL/6J mice were twice intraperitoneally injected with the MPTP (36 mg/kg, 20 mg/kg) neurotoxin to induce parkinsonism. rhEPO (200 000 IU) was injected in the left striatum of PD affected mice 10 days after toxin administration. Dopaminergic recovery was assessed via immunofluorescence. Our results indicate that rhEPO restores cell viability and contributes to dopaminergic recovery through a rescue of tyrosine hydroxylase (TH) and nuclear receptor related-1 (NURR1) markers. Moreover, rhEPO treatment rescues the PD-induced morphological damage to mitochondria and acutely promotes a significant rescue of mitochondrial respiration, with an enhancement of the glycolytic rate, contributing to improve the ATP level in MPP+-challenged cells. In PD mice, EPO infusion improves the outcome of behavioral tests starting at day 3 after administration. This functional recovery is associated with both rescue of TH, NURR1 and decrease of GFAP, IBA1 and MOMA, that document a relevant action of EPO against neuroinflammation markers. We conclude that the redox imbalance and neuroinflammation associated to PD may be successfully treated by EPO.