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Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease.

Authors
Sriram-K; Matheson-JM; Benkovic-SA; Miller-DB; Luster-MI; O'Callaghan-P
Source
FASEB J 2002 Sep; 16(11):1474-1476
NIOSHTIC No.
20023020
Abstract
The pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF-alpha in PD, we examined the effects of the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild-type (+/+) mice resulted in a time-dependent expression of TNF-alpha in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR-DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF-alpha is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF-alpha is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP-induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD.
Keywords
Neurotoxicity; Tumors; Neurotoxins; Laboratory-animals; Animal-studies; Animals; Neuromuscular-function; Neuromotor-function; Neurotoxic-effects
Contact
James P. O'Callaghan, HELD/TMBB, CDC-NIOSH, Mailstop L-3014, 1095 Willowdale Road, Morgantown, WV 26505, USA
CODEN
FAJOEC
CAS No.
28289-54-5
Publication Date
20020901
Document Type
Journal Article
Email Address
jdo5@cdc.gov
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Issue of Publication
11
ISSN
0892-6638
NIOSH Division
HELD
Source Name
The FASEB Journal
State
WV
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