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Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury

Research output: Contribution to journalArticle

Claire-Marie Rangon, Anne-Laure Schang, Juliette Van Steenwinckel, Leslie Schwendimann, Sophie Lebon, Tingting Fu, Libo Chen, Veronique Beneton, Nathalie Journiac, Pierrette Young-Ten, Thomas Bourgeois, Johanna Maze, Boris Matrot, Ana A Baburamani, Veena Supramaniam, Carina Mallard, Lionel Trottet, A David Edwards, Henrik Hagberg, Bobbi Fleiss & 3 more Jingjun Li, Tsu Tshen Chuang, Pierre Gressens

Original languageEnglish
JournalBrain, Behavior, and Immunity
Early online date12 Sep 2018
DOIs
Publication statusE-pub ahead of print - 12 Sep 2018

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Abstract

Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7mg/kg or 20mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.

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