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

• Published in: Neurotoxicity research Vol. 5; no. 5; pp. 339 - 354
• Main Authors: McPherson, Christopher A, Kubik, Julie, Wine, Robert N, D'Hellencourt, Christian Lefebvre, Harry, G Jean
• Format: Journal Article
• Language: English
• Published: United States Springer Verlag 2003
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Cell Division - drug effects; Cyclin A - biosynthesis; Cyclin A - metabolism; Cyclin B - biosynthesis; Cyclin B - metabolism; Cyclin D1 - biosynthesis; Cyclin D1 - metabolism; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; Fluorescent Antibody Technique; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Human health and pathology; In Situ Hybridization; Life Sciences; Male; Mice; Nerve Tissue Proteins - biosynthesis; Neuroglia - drug effects; Neuroglia - metabolism; Neuroglia - pathology; Nuclease Protection Assays; RNA, Messenger - biosynthesis; Trimethyltin Compounds - toxicity; Tumor Necrosis Factor-alpha - biosynthesis; Astrocytes; Cyclin; gyrus; Glia; Trimethyltin; Hippocampus; Dentate
• DOI: 10.1007/bf03033154
• EISSN: 1476-3524
• ISSN: 1029-8428

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 hrs. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-alpha, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-alpha 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.