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

Emily Grace Baxi, Ying Cheng, Jo Anne E Natale

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1356-1368
Number of pages13
JournalJournal of Neuroscience Research
Volume87
Issue number6
DOIs
StatePublished - May 1 2009

Fingerprint

Minocycline
Metallothionein
Neurons
Brain
Microglia
Wounds and Injuries
Geniculate Bodies
Calpain
p38 Mitogen-Activated Protein Kinases
Visual Cortex
Knockout Mice
Interferons
Genes
DNA Damage
Intercellular Signaling Peptides and Proteins
Phosphorylation
Research Personnel
Cytokines
Growth

Keywords

  • Metallothionein
  • Microglia
  • Minocycline
  • Traumatic brain injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Deleterious effects of minocycline after in vivo target deprivation of thalamocortical neurons in the immature, metallothionein-deficient mouse brain. / Baxi, Emily Grace; Cheng, Ying; Natale, Jo Anne E.

In: Journal of Neuroscience Research, Vol. 87, No. 6, 01.05.2009, p. 1356-1368.

Research output: Contribution to journalArticle

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