Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury
Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury
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DOI：
10.1093/brain/awx312
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发表时间：
2018-01-01
期刊：
影响因子：
14.5
通讯作者：
Fancy, Stephen P. J.
中科院分区：
文献类型：
--
作者：
Cree, Bruce A. C.;Niu, Jianqin;Fancy, Stephen P. J.
缺氧可损伤由轴突和髓鞘生成少突胶质细胞组成的脑白色物质束，导致新生儿脑瘫和成人迟发性缺氧后白质脑病（DPHL）。在这些情况下，白色物质损伤后可能会出现髓鞘再生，但髓鞘形成通常失败，并且是固定脱髓鞘病变的重要促成因素，随后发生永久性神经损伤。非髓鞘化少突胶质前体细胞经常在病变中大量发现，但不能成熟，这表明少突胶质前体细胞分化停滞是缺氧中髓鞘形成失败的关键因素。我们报告了一例成年患者，他患上了罕见的DPHL，并在使用氯马斯汀（一种广泛使用的抗组胺药，在临床前模型中可促进少突胶质细胞前体细胞分化）治疗后几乎完全康复。这表明在临床上更普遍的新生儿缺氧损伤中可能有治疗益处，并且我们在小鼠新生儿缺氧损伤中证明氯马斯汀显著促进少突胶质细胞前体细胞分化、髓鞘形成并改善功能恢复。我们发现，它在缺氧中的作用是少突胶质细胞特异性通过对少突胶质细胞前体细胞上的M1毒蕈碱受体的影响。我们建议氯马斯汀作为一种潜在的治疗缺氧性脑损伤相关的白色物质损伤和少突胶质细胞前体细胞成熟阻滞。
Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest.