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

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; Jingjun Li; Tsu Tshen Chuang; Pierre Gressens

doi:10.1016/j.bbi.2018.09.017

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

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 FleissJingjun Li, Tsu Tshen Chuang, Pierre Gressens

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

498 Downloads (Pure)

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.

Original language	English
Journal	Brain, Behavior, and Immunity
Early online date	12 Sept 2018
DOIs	https://doi.org/10.1016/j.bbi.2018.09.017
Publication status	E-pub ahead of print - 12 Sept 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bbi.2018.09.017

Myelination induction by a histamine_RANGON_Firstonline12September2018_GREEN AAMAccepted author manuscript, 38.1 MB

Cite this

Rangon, C.-M., Schang, A.-L., Van Steenwinckel, J., Schwendimann, L., Lebon, S., Fu, T., Chen, L., Beneton, V., Journiac, N., Young-Ten, P., Bourgeois, T., Maze, J., Matrot, B., Baburamani, A. A., Supramaniam, V., Mallard, C., Trottet, L., Edwards, A. D., Hagberg, H., ... Gressens, P. (2018). Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury. Brain, Behavior, and Immunity. Advance online publication. https://doi.org/10.1016/j.bbi.2018.09.017

@article{1b17a9c9df35427cb6881e46d376bf14,

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

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.",

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

year = "2018",

month = sep,

day = "12",

doi = "10.1016/j.bbi.2018.09.017",

language = "English",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "ACADEMIC PRESS INC",

}

Rangon, C-M, Schang, A-L, Van Steenwinckel, J, Schwendimann, L, Lebon, S, Fu, T, Chen, L, Beneton, V, Journiac, N, Young-Ten, P, Bourgeois, T, Maze, J, Matrot, B, Baburamani, AA , Supramaniam, V, Mallard, C, Trottet, L, Edwards, AD , Hagberg, H , Fleiss, B, Li, J, Tshen Chuang, T & Gressens, P 2018, 'Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury', Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2018.09.017

TY - JOUR

T1 - Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury

AU - Rangon, Claire-Marie

AU - Schang, Anne-Laure

AU - Van Steenwinckel, Juliette

AU - Schwendimann, Leslie

AU - Lebon, Sophie

AU - Fu, Tingting

AU - Chen, Libo

AU - Beneton, Veronique

AU - Journiac, Nathalie

AU - Young-Ten, Pierrette

AU - Bourgeois, Thomas

AU - Maze, Johanna

AU - Matrot, Boris

AU - Baburamani, Ana A

AU - Supramaniam, Veena

AU - Mallard, Carina

AU - Trottet, Lionel

AU - Edwards, A David

AU - Hagberg, Henrik

AU - Fleiss, Bobbi

AU - Li, Jingjun

AU - Tshen Chuang, Tsu

AU - Gressens, Pierre

PY - 2018/9/12

Y1 - 2018/9/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.bbi.2018.09.017

DO - 10.1016/j.bbi.2018.09.017

M3 - Article

SN - 0889-1591

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this