Neurotoxicity Research

, Volume 5, Issue 5, pp 339–354

Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage

  • Christopher A. McPherson
  • Julie Kubik
  • Robert N. Wine
  • Christian Lefebvre D'Hellencourt
  • G. Jean Harry
Article

Abstract

The interactions of glia and neurons during injury and subsequent neurodegeneration are a subject of interest both in disease and chemical-induced brain injury. One such model is the prototypical hippocampal toxicant trimethyltin (TMT). An acute injection of TMT (2.0 mg/kg, i.p.) to postnatal day 21 CD-1 male mice produced neuronal necrosis and loss of dentate granule cells, astrocyte hypertrophy, and microglia activation in the hippocampus within 24 h. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-α, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-α mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h. Immunohistochemistry suggested a cellular localization of cyclin A to microglia in the region of neuronal necrosis in the dentate, cyclin B in glial cells in juxtaposition to neurons in the hilus of the hippocampus and cyclin D1 to non-glial cells in the dentate. mRNA levels for cyclin D1 were elevated approximately 1.5-fold by 72 h as determined by RNase protection assay. No changes were seen in mRNA levels for cyclins E, F, G1, G2, H or I nor cyclin dependent kinases. These elevations are not associated with proliferation of microglia as determined by BrdU incorporation and Ki-67 immunohistochemistry. Upregulation of cell cycle genes was associated with cellular processes other than proliferation and may contribute to the differentiation of microglia to a phagocytic phenotype. These data suggest an integrated role for cell cycle regulation of neural cells in the manifestation of hippocampal pathophysiology.

Keywords

Cyclin Trimethyltin Glia Astrocytes Hippocampus Dentate gyrus 

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Copyright information

© FP Graham Publishing Co 2003

Authors and Affiliations

  • Christopher A. McPherson
    • 1
  • Julie Kubik
    • 1
  • Robert N. Wine
    • 1
  • Christian Lefebvre D'Hellencourt
    • 1
  • G. Jean Harry
    • 1
  1. 1.Neurotoxicology GroupNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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