Neuroprotective role for Erythropoietin in Parkinson’s Disease: evidences from in vitro and in vivo models of the disease

INTRODUCTION: Parkinson's Disease (PD) is the second most common neurodegenerative disorder, and it is characterized by the selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Existing therapies are only symptomatic, and their efficiency is reduced during disease progression. For this reason, in the last years the role of Erythropoietin (EPO), a type I cytokine, is gaining more and more relevance, due to its possible neuroprotective action. In this study, we focused on the neuroprotective role of EPO in both in vitro and in vivo models of the disease. METHODS: As an in vivo PD murine model, C5BL/6J mice were twice intraperitoneally injected with the MPTP (36 mg/kg, 20 mg/kg) neurotoxin to induce parkinsonism. EPO (200 000 IU) was injected in the left striatum of PD affected mice 10 days after toxin administration. As an in vitro model of PD, SH-SY5Y cell line were treated with MPP+ for 24 hours. RESULTS: We investigated the expression of dopaminergic markers, TH and NURR1 by immunofluorescence, and we observed a decrease of their expression in the striatum of MPTP treated mice. These were restored after EPO’s infusion. We also report an increased gliosis in MPTP PD mice, which results reduced after EPO treatment. Moreover, we set up an in vitro model of PD and we report that EPO leads to the recovery of dopaminergic targets TH and NURR1 in the in vitro cellular model, investigated by Real Time PCR, Western Blot and immunofluorescence. We also studied EPO’s role in mitochondrial health, showing how there is an effective recovery of mitochondria in EPO co-treatment, with respect to the pathological condition. Indeed, these observations were corroborated both by Mitotracker staining and Transmission Electron Microscopy, observing a qualitative and quantitative recovery. Finally, we demonstrated that SH-SY5Y cells express a specific truncated EPOR isoform of 37 kDa, induced in the PD pathological condition, and which resulted strongly expressed in EPO cotreatment, suggesting the existence of a new EPO/EPOR pathway, not yet deeply described. DISCUSSION & CONCLUSIONS: Taken together these results demonstrated an important role for EPO in the in vivo and the vitro PD models, suggesting that EPO could exert a neuroprotective action against MPTP-induced parkinsonism and have a specific role in the recovery of dopaminergic neurons.