Erythropoietin protects against 6-hydroxydopamine-induced dopaminergic cell death

Authors

  • Armando P. Signore,

    1. Departments of Neurology
    2. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Zhongfang Weng,

    1. Departments of Neurology
    2. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Teresa Hastings,

    1. Departments of Neurology
    2. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Amber D. Van Laar,

    1. Departments of Neurology
    2. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Qinghua Liang,

    1. Departments of Neurology
    2. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Yong J. Lee,

    1. Pharmacology
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  • Jun Chen

    1. Departments of Neurology
    2. Pharmacology
    3. Institute of Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    4. Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA
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Address correspondence and reprint requests to Dr Jun Chen, Department of Neurology, S-507, Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. E-mail: chenj2@upmc.edu

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.

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