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Am J Pathol. 2015 Sep;185(9):2364-78. doi: 10.1016/j.ajpath.2015.05.016. Epub 2015 Jul 22.

Modulation of Sox10, HIF-1α, Survivin, and YAP by Minocycline in the Treatment of Neurodevelopmental Handicaps following Hypoxic Insult.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
2
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Division of Cancer Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
3
Department Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: joseph.madri@yale.edu.

Abstract

Premature infants are at an increased risk of developing cognitive and motor handicaps due to chronic hypoxia. Although the current therapies have reduced the incidence of these handicaps, untoward side effects abound. Using a murine model of sublethal hypoxia, we demonstrated reduction in several transcription factors that modulate expression of genes known to be involved in several neural functions. We demonstrate the induction of these genes by minocycline, a tetracycline antibiotic with noncanonical functions, in both in vitro and in vivo studies. Specifically, there was induction of genes, including Sox10, Hif1a, Hif2a, Birc5, Yap1, Epo, Bdnf, Notch1 (cleaved), Pcna, Mag, Mobp, Plp1, synapsin, Adgra2, Pecam1, and reduction in activation of caspase 3, all known to affect proliferation, apoptosis, synaptic transmission, and nerve transmission. Minocycline treatment of mouse pups reared under sublethal hypoxic conditions resulted in improvement in open field testing parameters. These studies demonstrate beneficial effects of minocycline treatment following hypoxic insult, document up-regulation of several genes associated with improved cognitive function, and support the possibility of minocycline as a potential therapeutic target in the treatment of neurodevelopmental handicaps observed in the very premature newborn population. Additionally, these studies may aid in further interpretation of the effects of minocycline in the treatment trials and animal model studies of fragile X syndrome and multiple sclerosis.

PMID:
26209807
DOI:
10.1016/j.ajpath.2015.05.016
[Indexed for MEDLINE]
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