Acta Neuropathologica

, Volume 116, Issue 1, pp 47–55

Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease

  • Luigi Zecca
  • Henrik Wilms
  • Sebastian Geick
  • Jan-Hendrik Claasen
  • Lars-Ove Brandenburg
  • Christian Holzknecht
  • Michele L. Panizza
  • Fabio A. Zucca
  • Günther Deuschl
  • Jobst Sievers
  • Ralph Lucius
Original Paper

DOI: 10.1007/s00401-008-0361-7

Cite this article as:
Zecca, L., Wilms, H., Geick, S. et al. Acta Neuropathol (2008) 116: 47. doi:10.1007/s00401-008-0361-7

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). It has been suggested that microglial inflammation augments the progression of PD. Neuromelanin (NM), a complex polymer pigment found in catecholaminergic neurons, has sparked interest because of the suggestion that NM is involved in cell death in Parkinson's disease, possibly via microglia activation. To further investigate the possible role of NM in the pathogenesis of PD, we conducted in vivo experiments to find out whether microglial cells become activated after injection of human neuromelanin (NM) into (1) the cerebral cortex or (2) the substantia nigra to monitor in this PD-relevant model both microglial activation and possible neurodegeneration. In this study, adult male Wistar rats received an intracerebral injection of either NM, bacterial lipopolysaccharide (LPS, positive control), phosphate-buffered saline (PBS, negative control) or colloidal gold suspension (negative particular control). After different survival times (1, 8 or 12 weeks), brain slices from the cerebral cortex or substantia nigra (SN, 1 week) were stained with Iba-1 and/or GFAP antibody to monitor microglial and astrocytic reaction, and with tyrosine hydroxylase (TH) to monitor dopaminergic cell survival (SN group only). The injection of LPS induced a strong inflammatory response in the cortex as well in the substantia nigra. Similar results could be obtained after NM injection, while the injection of PBS or gold suspension showed only moderate or no glial activation. However, the inflammatory response declined during the time course. In the SN group, there was, apart from strong microglia activation, a significant dopaminergic cell loss after 1 week of survival time. Our findings clearly indicate that extracellular NM could be one of the key molecules leading to microglial activation and neuronal cell death in the substantia nigra. This may be highly relevant to the elucidation of therapeutic strategies in PD.

Keywords

Microglia Neurodegenerative disease Dopaminergic cell death 

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Luigi Zecca
    • 3
  • Henrik Wilms
    • 2
    • 4
  • Sebastian Geick
    • 1
  • Jan-Hendrik Claasen
    • 1
  • Lars-Ove Brandenburg
    • 1
  • Christian Holzknecht
    • 1
  • Michele L. Panizza
    • 3
  • Fabio A. Zucca
    • 3
  • Günther Deuschl
    • 2
  • Jobst Sievers
    • 1
  • Ralph Lucius
    • 1
  1. 1.Department of AnatomyUniversity of KielKielGermany
  2. 2.Department of NeurologyUniversity of KielKielGermany
  3. 3.Institute of Biomedical TechnologiesSegrate-MilanItaly
  4. 4.Department of NeurologyUniversity of HeidelbergHeidelbergGermany

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