Erythropoietin protects against 6‐hydroxydopamine‐induced dopaminergic cell death

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopaminergic neurons. In the present study, erythropoietin, a trophic factor that has both hematopoietic and neural protective characteristics, was investigated for its capacity to protect dopaminergic neurons in experimental Parkinson's disease. Using both the dopaminergic cell line, MN9D, and primary dopamine neurons, we show that erythropoietin (1-3 U/mL) is neuroprotective against the dopaminergic neurotoxin, 6-hydroxydopamine. Protection was mediated by the erythropoietin receptor, as neutralizing anti-erythropoietin receptor antibody abrogated the protection. Activation of Akt/protein kinase B (PKB), via the phosphoinositide 3-kinase pathway, is a critical mechanism in erythropoietin-induced protection, while activation of extracellular signal-regulated kinase (ERK)1/2 contributes only moderately. Indeed, transfection of constitutively active Akt/PKB into dopaminergic cells was sufficient to protect against cell death. Furthermore, erythropoietin diminished markers of apoptosis in MN9D cells, including caspase 9 and caspase 3 activation and internucleosomal DNA fragmentation, suggesting that erythropoietin interferes with the apoptosis-execution process. When erythropoietin was administered to mice unilaterally lesioned with 6-hydroxydopamine, it prevented the loss of nigral dopaminergic neurons and maintained striatal catecholamine levels for at least 8 weeks. Erythropoietin-treated mice also had significantly reduced behavioral asymmetries. These studies suggest that erythropoietin can be an effective neuroprotective agent for dopaminergic neurons, and may be useful in reversing behavioral deficits associated with Parkinson's disease.

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

“…In addition, EPO receptor is abundantly expressed in adult dopaminergic neurons [15] , suggesting a direct effect of EPO on neurons. EPO can also protect dopaminergic neurons against the neurotoxicities of MPTP and 6-hydroxydopamine, and significantly reverse the corresponding behavioral deficits in mice [8,10] . The protection of EPO in the central nervous system is mediated by a series of cellular pathways that maintain intricate links between one another.…”

“…It has been also reported that EPO displays efficient neuroprotective properties in a spectrum of different animal models, including ischemia/hypoxia, excitotoxic paradigms, traumatic brain and spinal cord injury, and retina/optic nerve damage in inflammatory/auto-immunological diseases [7] . Recent studies have revealed a possible protective role of EPO in Parkinson's disease [8][9][10] .…”

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

“…It has been previously reported that a compound with a trophic property can induce the proliferation of MN9D cells and is neuroprotective against 6-OHDA-induced cell death. 42 The morphology of the cells under different treatment regimens with 6-OHDA and MPP+ is shown in Figure 5. ingly, the results indicate that Ropinirole showed very weak to no neuroprotection in reversing the toxicity of both 6-OHDA and MPP+ (Figures 3F and 4D).…”

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

“…Transduction profiles of the AAV9 vectors after striatal injections were similar to previous findings using AAV2 or AAV5 vectors. 32 It has been suggested that EPO exerts its neuroprotective effects on CNS neurons through multiple mechanisms, including anti-apoptosis, 5,33 anti-inflammation, 34 inhibition of glutamate release, inhibition of reactive oxygen species formation, 35 activation of Akt/ protein kinase B through the phosphoinositide 3-kinase pathway, 5 and activation of Janus kinase-2 and nuclear factor-kB signaling pathways. 36 We have recently showed that intrastriatal administration of EPO protects nigral DA neurons from cell death induced by 6-OHDA in part through an anti-inflammatory mechanism.…”

“…Accumulating evidence has shown that EPO protein and EPO receptors (EPORs) exist in CNS neurons. 1,2 EPO has been found to protect dopaminergic (DA) neurons from experimental insults and druginduced degeneration, 1,[3][4][5][6] suggesting its therapeutic potential for Parkinson's disease (PD). In our previous study with EPO protein infusions, although intrastriatal delivery was protective, systemic administration of EPO did not protect DA neurons from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of PD.…”