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Deleterious effects of minocycline after in vivo target deprivation of thalamocortical neurons in the immature, metallothionein-deficient mouse brain

Authors

  • Emily G. Potter,

    Corresponding author
    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
    2. Neuroscience Program, Institute for Biomedical Sciences, George Washington University, Washington, DC
    • Department of Neurology, Johns Hopkins School of Medicine, 600 North Wolfe Street, Pathology 627, Baltimore, MD 21287
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  • Ying Cheng,

    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
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  • JoAnne E. Natale

    1. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC
    2. Neuroscience Program, Institute for Biomedical Sciences, George Washington University, Washington, DC
    3. Center for Neuroscience Research, Children's National Medical Center, Washington, DC
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Abstract

Compared with adults, immature metallothionein I and II knockout (MT−/−) mice incur greater neuronal loss and a more rapid rate of microglia accumulation after target deprivation-induced injury. Because minocycline has been proposed to inhibit microglial activation and associated production of neuroinflammatory factors, we investigated its ability to promote neuronal survival in the immature, metallothionein-deficient brain. After ablation of the visual cortex, 10-day-old MT−/− mice were treated with minocycline or saline and killed 24 or 48 hr after injury. By means of stereological methods, the number of microglia and neurons were estimated in the ipsilateral dorsal lateral geniculate nucleus (dLGN) by an investigator blinded to the treatment. No effect on neuronal survival was observed at 24 hr, but 48 hr after injury, an unanticipated but significant minocycline-mediated increase in neuronal loss was detected. Further, while failing to inhibit microglial accumulation, minocycline treatment increased the proportion of amoeboid microglia in the ipsilateral dLGN. To understand the molecular mechanisms underlying this neurotoxic response, we identified minocycline-mediated changes in the expression of three potentially proapoptotic/inflammatory genes: growth arrest– and DNA damage–inducible gene 45γ (GADD45γ); interferon-inducible protein 1 (IFI1), and cytokine-induced growth factor. We also observed increased mitogen-activated protein kinase p38 phosphorylation with minocycline treatment. Although minocycline inhibited calpain activity at 12 hr after injury, this effect was not sustained at 24 hr. Together, these results help to explain how minocycline has a deleterious effect on neuronal survival in this injury model. © 2008 Wiley-Liss, Inc.

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