| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1
Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA
2Correspondence: CDC-NIOSH, M/S L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA. E-mail: jdo5{at}cdc.gov
Enhanced expression of tumor necrosis factor (TNF) -
, 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- 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-, 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- 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- 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- in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus.—Sriram, K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster, M. I., O’Callaghan, J. P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-.
Key Words: brain • neurodegeneration • neuroinflammation • neuroprotection • microglia
This article has been cited by other articles:
|
|
 |
|
  V. Kaushal and L. C. Schlichter Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra J. Neurosci., February 27, 2008; 28(9): 2221 - 2230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Reynolds, R. Banerjee, J. Liu, H. E. Gendelman, and R. L. Mosley Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease J. Leukoc. Biol., November 1, 2007; 82(5): 1083 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bushell The emergence of proteinase-activated receptor-2 as a novel target for the treatment of inflammation-related CNS disorders J. Physiol., May 15, 2007; 581(1): 7 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. McCoy, T. N. Martinez, K. A. Ruhn, D. E. Szymkowski, C. G. Smith, B. R. Botterman, K. E. Tansey, and M. G. Tansey Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J. Neurosci., September 13, 2006; 26(37): 9365 - 9375. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
