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Brain. 2018 Jan 1;141(1):85-98. doi: 10.1093/brain/awx312.

Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury.

Author information

1
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California at San Francisco, San Francisco, CA 94158, USA.
2
Department of Pediatrics, University of California at San Francisco, San Francisco, CA 94158, USA.
3
Department of Histology and Embryology, Collaborative Innovation Center for Brain Research, Third Military Medical University, Chongqing 400038, China.
4
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AH, UK.
5
Department of Ophthalmology, University of California at San Francisco, San Francisco, CA 94158, USA.
6
Division of Neonatology, University of California at San Francisco, San Francisco, CA 94158, USA.
7
Newborn Brain Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA.

Abstract

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.

KEYWORDS:

cerebral palsy; clemastine; hypoxia; myelination; oligodendrocyte

PMID:
29244098
PMCID:
PMC6394402
DOI:
10.1093/brain/awx312
[Indexed for MEDLINE]
Free PMC Article

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