Ciprofloxacin prevents myelination delay in neonatal rats subjected to E. coli sepsis

Authors

  • Gauthier Loron MD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Paul Olivier PhD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Hélène See MD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. Equipe d'accueil EA 3105, Université Paris Diderot, Paris, France
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  • Nolwenn Le Saché MD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. Equipe d'accueil EA 3105, Université Paris Diderot, Paris, France
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  • Leslie Angulo,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. Equipe d'accueil EA 3105, Université Paris Diderot, Paris, France
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  • Valérie Biran MD, PhD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. PremUP, Paris, France
    3. NICU, Université Paris Diderot, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Nadège Brunelle PhD,

    1. INSERM IFR 65 IRSSA, Hôpital Saint Antoine, APHP, Paris, France
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  • Bernadette Besson-Lescure PhD,

    1. INSERM IFR 65 IRSSA, Hôpital Saint Antoine, APHP, Paris, France
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  • Marie-Dominique Kitzis PhD,

    1. Fondation Hôpital Saint-Joseph, Paris, France
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  • Julien Pansiot MS,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Edouard Bingen MD,

    1. Equipe d'accueil EA 3105, Université Paris Diderot, Paris, France
    2. Department of Microbiology, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Pierre Gressens MD, PhD,

    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. INSERM UMR 676, Université Paris Diderot, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    3. PremUP, Paris, France
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  • Stéphane Bonacorsi MD, PhD,

    1. Equipe d'accueil EA 3105, Université Paris Diderot, Paris, France
    2. Department of Microbiology, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
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  • Olivier Baud MD, PhD

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research) AVENIR R05230HS, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    2. PremUP, Paris, France
    3. NICU, Université Paris Diderot, Hôpital Robert Debré, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France
    • INSERM, AVENIR-U676, Hôpital Robert Debré, 48 Blvd Sérurier, F-75019 Paris, France
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Abstract

Objective

Perinatal infections and the systemic inflammatory response to them are critical contributors to white matter disease (WMD) in the developing brain despite the use of highly active antibiotics. Fluoroquinolones including ciprofloxacin (CIP) have intrinsic anti-inflammatory effects. We hypothesized that CIP, in addition to its antibacterial activity, could exert a neuroprotective effect by modulating white matter inflammation in response to sepsis.

Methods

We adapted an Escherichia coli sepsis model to 5-day-old rat pups (P5), to induce white matter inflammation without bacterial meningitis. We then compared the ability of CIP to modulate inflammatory-induced brain damage compared with cefotaxime (CTX) (treatment of reference).

Results

Compared with CTX, CIP was associated with reduced microglial activation and inducible nitric oxide synthase (iNOS) expression in the developing white matter in rat pups subjected to E. coli sepsis. In addition to reducing microglial activation, CIP was able to prevent myelination delay induced by E. coli sepsis and to promote oligodendroglial survival and maturation. We found that E. coli sepsis altered the transcription of the guidance molecules semaphorin 3A and 3F; CIP treatment was capable of reducing semaphorin 3A and 3F transcription levels to those seen in uninfected controls. Finally, in a noninfectious white matter inflammation model, CIP was associated with significantly reduced microglial activation and prevented WMD when compared to CTX.

Interpretation

These data strongly suggest that CIP exerts a beneficial effect in a model of E. coli sepsis-induced WMD in rat pups that is independent of its antibacterial activity but likely related to iNOS expression modulation. ANN NEUROL 2011

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