PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France.
PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France; UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, F-75006 Paris, France.
Brain Behav Immun. 2018 Nov;74:265-276. doi: 10.1016/j.bbi.2018.09.017. Epub 2018 Sep 12.
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.
每年有 1500 万婴儿早产，其中相当数量的婴儿患有与白质损伤（WMI）相关的永久性神经损伤。早产本身的一个主要原因，也是 WMI 严重程度的预测因素，是母体-胎儿感染-炎症的暴露，如绒毛膜羊膜炎。目前还没有针对这种 WMI 的神经治疗方法。为了满足这一医疗需求，将在其他白质损伤模型中具有疗效的药物重新用于治疗是一种有吸引力的策略。因此，我们测试了 GSK247246（一种 H3R 拮抗剂/反向激动剂）在炎症介导的早产婴儿 WMI 模型中的疗效，该模型再现了人类脑损伤的主要临床特征，即少突胶质细胞成熟停滞、小胶质细胞反应性和少突胶质细胞脱髓鞘。通过模拟母体-胎儿感染-炎症的作用并引发神经炎症来诱导 WMI。我们在相当于人类妊娠晚期的时间点（出生后第 1 天至第 5 天），通过腹腔内注射白细胞介素-1β（IL-1β）来诱导这种过程。在神经炎症得到很好的建立后（出生后第 6 天），我们开始用 GSK247246 进行治疗（腹腔内注射 7mg/kg 或 20mg/kg），并通过腹腔内注射每天两次至第 10 天。在第 10 天和第 30 天，通过基因和蛋白质分析评估结果。低剂量的 GSK247246（7mg/kg）导致髓鞘标志物（髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）的密度）的蛋白质表达恢复，并减少巨细胞和小胶质细胞增生（离子适应蛋白（IBA1）和神经胶质纤维酸性蛋白（GFAP）的密度）。我们的结果证实了针对 H3R 治疗 WMI 的神经治疗效果，这在多发性硬化症的铜泽酮模型和最近报道的复发性缓解型多发性硬化症患者的临床试验中得到了验证。需要进一步的工作来开发这种药物的缓释策略，并在早产婴儿 WMI 的大动物模型中测试其疗效。
