title: Modulation of Sox10, HIF-1α, Survivin, and YAP by Minocycline in the Treatment of Neurodevelopmental Handicaps following Hypoxic Insult.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Division of Cancer Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.affiliation: Department Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Rachael
authors.initials: R
authors.lastname: Couture
authors.affiliation: Department Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwartz
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: joseph.madri@yale.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D009103:Multiple Sclerosis / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D055757:SOXE Transcription Factors / Q000378:metabolism*; D000077022:Survivin; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117749:Birc5 protein, mouse; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D000077022:Survivin; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D008911:Minocycline