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 7 mg/kg or 20 mg/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.

Interneuron Development Is Disrupted in Preterm Brains With Diffuse White Matter Injury: Observations in Mouse and Human

“…The utility of the mice with IL-1β-induced inflammation and subsequent diffusion white matter injury used here is that the injury is broadly comparable in nature to that seen in our patient samples. Specifically, this model displays the hallmarks of injury observed in contemporary preterm born infants: hypomyelination, axonopathy, oligodendrocyte dysmaturation and also, reported here and previously, no gross cortical injury evidenced by no change in cortical neuronal number (Favrais et al, 2011; Schang et al, 2014; Krishnan et al, 2017; Rangon et al, 2018). In this model, females have a less severe and more transient phenotype, which is why they were not used in this study (unpublished data), suggesting a bias seen in the animal model similar to that observed in the human population (Marlow et al, 2005).…”

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

“…To validate the in vivo neurotherapeutic efficacy of our novel nanocarrier-mediated WNT agonist therapy, we assessed the IL-1β-induced myelination deficit by measuring Mbp mRNA at P10, MBP protein via western blotting at P15 and axonal myelination via electron microscopy at P30. We have previously shown in this model that there is an accumulation of immature oligodendrocytes (NG2+ and PDGFRa+), reduced small calibre axonal myelination and reduced expression of myelin proteins (Favrais et al, 2011;Schang et al, 2014;Rangon et al, 2018).Treatment with i.p. 3DNA L803mts Cy3 significantly prevented the IL-1β-induced reduction in Mbp mRNA ( Figure 7B) and alleviated the IL-1β-induced reduction in MBP proteins ( Figure 7C,D, Supp Figure 7A).…”

Postnatal Nutrition to Improve Brain Development in the Preterm Infant: A Systematic Review From Bench to Bedside

“…In addition to timing, also inclusion of an inflammatory component is thought to be key to the development of translational animal models of EoP. In recent years, rodent models of EoP have been developed (Zeng et al, 2018), including several multiple hit models that combined fetal inflammation with post-natal hypoxia (van Tilborg et al, 2018a) or multiple post-natal injections of cytokines (Rangon et al, 2018). Also larger animal models of EoP have been developed, mostly using preterm lambs (Li et al, 2016; Wassink et al, 2017; Gussenhoven et al, 2018), piglets (Andersen et al, 2016; Buddington et al, 2018), and baboons (Griffith et al, 2012).…”