Neurochemical Research

, Volume 31, Issue 1, pp 85–94

Reactive Macrophages Increase Oxidative Stress and Alpha-Synuclein Nitration During Death of Dopaminergic Neuronal Cells in Co-Culture: Relevance to Parkinson’s Disease

Article

DOI: 10.1007/s11064-005-9233-x

Cite this article as:
Shavali, S., Combs, C.K. & Ebadi, M. Neurochem Res (2006) 31: 85. doi:10.1007/s11064-005-9233-x

Abstract

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons and a substantial decrease in the neurotransmitter dopamine in the nigro-striatal region of the brain. Increased markers of oxidative stress, activated microglias and elevated levels of pro-inflammatory cytokines have been identified in the brains of patients with PD. Although the precise mechanism of loss of neurons in PD remains unclear, these findings suggest that microglial activation may contribute directly to loss of dopaminergic neurons in PD patients. In the present study, we tested the hypothesis that activated microglia induces nitric oxide-dependent oxidative stress which subsequently causes death of dopaminergic neuronal cells in culture. We employed lipopolysaccharide (LPS) stimulated mouse macrophage cells (RAW 264.7) as a reactive microglial model and SH-SY5Y cells as a model for human dopaminergic neurons. LPS stimulation of macrophages led to increased production of nitric oxide in a time and dose dependent manner as well as subsequent generation of other reactive nitrogen species such as peroxynitrite anions. In co-culture conditions, reactive macrophages stimulated SH-SY5Y cell death characterized by increased peroxynitrite concentrations and nitration of alpha-synuclein within SH-SY5Y cells. Importantly 1400W, an inhibitor of the inducible nitric oxide synthase provided protection from cell death via decreasing the levels of nitrated alpha-synuclein. These results suggest that reactive microglias could induce oxidative stress in dopaminergic neurons and such oxidative stress may finally lead to nitration of alpha-synuclein and death of dopaminergic neurons in PD.

Keywords

Parkinson’s diseaseinflammationoxidative stressalpha-synuclein

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Shaik Shavali
    • 1
  • Colin K. Combs
    • 1
  • Manuchair Ebadi
    • 1
    • 2
    • 3
  1. 1.Departments of Pharmacology, Physiology and TherapeuticsUniversity of North Dakota School of Medicine and Health SciencesGrand ForksUSA
  2. 2.Departments of Pharmacology, Physiology and Therapeutics and of Clinical NeuroscienceUniversity of North Dakota School of Medicine and Health SciencesGrand ForksUSA
  3. 3.FACCP, Chester-Fritz Distinguished Professor of Pharmacology and of Clinical Neuroscience, Associate Vice-President for Medical ResearchUniversity of North Dakota School of Medicine & Health SciencesGrand ForksUSA