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Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha1.

Authors
Sriram-K; Matheson-JM; Benkovic-SA; Miller-DB; Luster-MI; O'Callaghan-JP
Source
FASEB J 2006 Apr; 20(6):670-682
NIOSHTIC No.
20030630
Abstract
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.
Keywords
Neurotoxicity; Neurotoxic-effects; Neurotoxicology; Neurotoxins; Neuropathology; Laboratory-animals; Animals; Animal-studies
Contact
CDC-NIOSH, M/S L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA
CODEN
FAJOEC
Publication Date
20060401
Document Type
Journal Article
Email Address
jdo5@cdc.gov
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Issue of Publication
6
ISSN
0892-6638
NIOSH Division
HELD
Source Name
The FASEB Journal
State
WV
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