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Role of proinflamatory cytokines in chemically-induced dopaminergic neurodegeration.

Toxicologist 2005 Mar; 84(Suppl 1):406
The pathogenic mechanisms underlying Parkinson's disease (PD) remain enigmatic. In an effort to identify early molecular events associated with PD, we profiled genomic and proteomic changes in the MPTP mouse model of PD. Specifically, we focused on the role of TNF-a, IL-1a, IL-6 and MCP-1, since enhanced expression of these proinflammatory cytokines and chemokines have been found in association with glial cells of patients with PD. MPTP caused a time-dependent increase in the mRNA expression of these cytokines in the striatum, but not in the hippocampus, and their expression preceded striatal dopaminergic degeneration (loss of dopamine and tyrosine hydroxylase), activation of JAK/STAT3 pathway and astrogliosis (upregulation of GFAP). Deficiency of the IL-6 gene did not alter striatal nerve terminal loss, but attenuated astrogliosis. However, in transgenic mice lacking TNFa receptors (TNFR-DKO), loss of striatal dopaminergic markers, phosphorylation of STAT3, upregulation of GFAP and astrocyte hypertrophy were nearly abolished. Interestingly, the lack of TNFá receptors exacerbated hippocampal neuronal damage (increased Fluoro Jade-B staining and loss of MAP-2 immunoreactivity) after MPTP. These findings implicate a region-specific role for TNF- in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus. From a Parkinson's disease perspective, these findings are suggestive of a primary role for TNF- in the pathogenesis of this disorder. As deficiency of TNF receptors or IL-6 gene attenuated phosphorylation of JAK-STAT3 and upregulation of GFAP, the findings implicate these signaling pathways in upregulation of GFAP. Since the activation of these pathways are early events in MPTP neurotoxicity, they may serve as potential therapeutic targets for modulation of neuronal loss and/or glial response following dopaminergic neurodegeneration.
Models; Laboratory-animals; Animals; Animal-studies; Pathogenesis; Pathogenicity; Neurotoxicity; Neurotoxic-effects; Therapeutic-agents; Brain-disorders
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The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana