Gene expression and cell-signaling events associated with toxicant-induced gliosis.
O'Callaghan-JP; Sriram-K; Luster-MI; Felschow-DM
Toxicologist 2002 Mar; 66(1-S):270
Astrogliosis represents a sensitive and early response of the nervous system to all types of neurotoxic injuries. The generality of the glial reaction, despite the target selectivity of specific neurotoxic insults, implies that there are common "signals" underlying this cellular response. The discovery and characterization of such signals would, therefore, broaden our understanding of molecular mechanisms underlying diverse neurotoxic responses and lead to early "predictors" of neurotoxic outcomes. We present evidence for candidate genes and signaling pathways underlying the glial response to neuronal damage resulting from exposure to the dopaminergic neurotoxicant, MPTP. In our model, a single 12.5 mg/kg dose of MPTP to the C57 B16/J mouse results in a 50% decline in dopamine and TH protein. The accompanying astrogliosis, as assessed by immunoassay of GFAP, begins at 12 hrs and peaks at 48 hrs post dosing. Striatal homogenates prepared from mice sacrificed by focused microwave irradiation to preserve steady-state phosphorylation revealed activation of the JAK-STAT pathway in the earliest phase of MPTP-induced gliosis. This effect was not observed in non-target regions and was completely reversed by neuroprotection with nomifensine. These results were indicative of effects specific to the neurotoxic condition and implicated potential upstream effectors in the JAK/MAP kinase modules, such as cytokines and trophic factors acting through the gp 130/Ras pathways. Gene array analysis revealed enhanced expression of TNF-alpha mRNA and the Ciphergen Protein Chips(trade name) platform of SELDI- TOF/MS analysis revealed a striatal-specific induction of 18 kD proteins consistent with induction of TNF-alpha, TNF-alpha receptor deficient mice showed complete neuroprotection against the neurotoxic effects of MPTP. Together these data show that a gene- protein- and phospho-specific antibody "arrays" can reveal novel mechanisms potentially underlying the glial response to neurotoxic insult.
Genes; Cell-growth; Cell-differentiation; Cellular-reactions; Cell-transformation; Neurotoxic-effects; Neurotoxicity; Neurotoxins; Neurotoxicology; Immune-reaction; Immunotoxins; Laboratory-animals; Protein-chemistry
The Toxicologist. Society of Toxicology 41st Annual Meeting and ToxExpo, March 17-21, 2002, Nashville, Tennessee