Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, National Health Commission and Chinese Academy of Medical Sciences Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, China.
J Exp Med. 2021 Jan 4;218(1). doi: 10.1084/jem.20191365.
Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-Cre) improved their differentiation, remyelination, and functional recovery following neonatal hypoxia-ischemia in mice. The regulation of oligodendrocyte differentiation by H2R is mediated by binding with Axin2, which leads to up-regulation of the Wnt/β-catenin signaling pathway. Furthermore, H2R antagonists also promoted oligodendrocyte differentiation and remyelination and the recovery of cognition and motor functions following neonatal hypoxia-ischemia. Thus, histamine H2R in oligodendrocytes could serve as a novel and effective therapeutic target for the retard of oligodendrocyte differentiation and remyelination following neonatal hypoxia-ischemia. The H2R antagonists may have potential therapeutic value for neonatal HIE.
新生儿缺氧缺血性脑病（HIE）伴有白质损伤的病理特征，常导致终生认知和神经行为功能障碍，但促进髓鞘形成的相关治疗方法仍不可用。我们发现组胺 H2 受体（H2R）在体外氧葡萄糖剥夺后，在少突胶质前体细胞阶段或成熟阶段不影响少突胶质细胞的情况下，负调节少突胶质细胞的分化率。值得注意的是，在分化的少突胶质细胞（Hrh2fl/fl；CNPase-Cre）中选择性缺失 H2R 基因（Hrh2）可改善其分化、髓鞘形成和功能恢复，在新生鼠缺氧缺血后。H2R 通过与 Axin2 结合来调节少突胶质细胞分化，从而上调 Wnt/β-catenin 信号通路。此外，H2R 拮抗剂也促进了新生鼠缺氧缺血后少突胶质细胞的分化和髓鞘形成，以及认知和运动功能的恢复。因此，少突胶质细胞中的组胺 H2R 可作为治疗新生儿缺氧缺血性脑病后少突胶质细胞分化和髓鞘形成延迟的新的有效治疗靶点。H2R 拮抗剂可能对新生儿 HIE 具有潜在的治疗价值。
