Deficiency of TNF Receptors Suppresses Microglial Activation and Alters the Susceptibility of Brain Regions to MPTP-Induced Neurotoxicity: Role of TNF-alpha1

Details

• Personal Author:
  Benkovic SA ; Luster MI ; Matheson JM ; Miller DB ; O'Callaghan JP ; Sriram K
• Description:
  Enhanced expression of tumor necrosis factor (TNF) -a, is associated with the neuropathological effects underlying disease-, trauma- and chemically induced neurodegeneration. Previously, we have shown that deficiency of TNF receptors protects against MPTP-induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF-a in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP-induced expression of microglia-derived factors, TNF-a, MCP-1, and IL-1, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF-a in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor-deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade-B staining (to identify degenerating neurons) and decreased microtubule-associated protein-2 (MAP-2) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF-a exerts a neurotrophic/neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and/or activity of microglia and microglia-derived factors may influence the region-specific role for this cell type. Taken together, our results are indicative of a region-specific and dual role for TNF-a in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Nervous System Occupational Health Safety
• Keywords:
  Animal-studies Laboratory-animals Neuropathology Neurotoxic-effects Neurotoxicity Neurotoxicology Neurotoxins
• ISSN:
  0892-6638
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  20
• Issue:
  6
• NIOSHTIC Number:
  nn:20030630
• Citation:
  FASEB J 2006 Apr; 20(6):670-682
• Contact Point Address:
  CDC-NIOSH, M/S L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA
• Email:
  jdo5@cdc.gov
• Federal Fiscal Year:
  2006
• Peer Reviewed:
  True
• Source Full Name:
  The FASEB Journal
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d13ba00109f6e60a38e2a24021f4d6e8f9b74f8911a7d91affba4f3d7e4538e106b6b8256cff601c6d834c6bf322c8b5b7c7418e112afcfe94789a776d876503
• Download URL:
  https://stacks.cdc.gov/view/cdc/191174/cdc_191174_DS1.pdf
• File Type:
  [PDF - 644.73 KB ]