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The trimethyltin model of hippocampal injury: gene array analysis reveals early and diverse changes in gene expression associated with neuronal injury and glial activation.
Little AR; O'Callaghan JP
Toxicologist 2004 Mar; 78(S-1):233-234
Damage to the CNS results in a complex series of molecular and cellular events involving the injured cells and their supportive environment. Understanding the earliest molecular changes associated with CNS injury offers the potential for developing neuroprotection strategies. The use of injury models with known cellular targets and a known time-course of damage facilitates this process. One such model is the hippocampal neurotoxicant, trimethyltin (TMT) which cause extensive loss of hippocampal neurons and an accompanying microglial and astroglial activation. Previously, we have shown that TMT causes a marked and early increase in the chemokine, Ccl2 (JE/MCP-1), coincident with microglial activation. Here were used the Affymetrix gene chip to obtain a more comprehensive portrait of gene expression changes during the earliest phases of TMT-induced damage. Changes seen on the chip were confirmed by Real Time PCR. After a single systemic dose of TMT (8.0 mg/kg) we confirmed an increase in expression of Ccl2 at two days post dosing which was not accompanied by an increase in its two receptors, CCR2 and CCR5. Increases in mRNA expression for STAT5a, GSK3alpha and several proteasome-related enzymes were observed at 2 and 5 days post TMT. Immuno-blot analysis for phospho-GSK3 alpha and beta showed dramatic increases in p-GSK 3 (alpha & beta) by day 5. These data suggest an involvement of the protein degradation pathway during early stages of neuronal degeneration. Cellular localization of STAT5a induction remains to be clarified but induction of GSK3 implicates activation of the Wnt pathway, for which the upstream effectors have been associated with gliosis. These results link protein degradation and cellular differentiation events to the earliest stages of neuronal injury.
Models; Genes; Neurotoxins; Neurotoxic-effects; Immunologic-disorders; Neurological-reactions; Central-nervous-system
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
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