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

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.

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

“…Clemastine is a first-generation histamine H1 receptor (HH1R) antagonist with good safety that features antiinflammatory effects and improves oligodendrocyte differentiation in hypoxic brain injury [14]. This drug also enhances myelination, rescues behavioral changes, and regulates the imbalance of pro-inflammatory cytokines including IL-1β [15,16].…”

Molecular and Therapeutic Aspects of Hyperbaric Oxygen Therapy in Neurological Conditions

“…Hence, hypoxia may result in a reduction in the number of cells differentiated to mature myelinating OLs. In Cree et al [60], administration of the drug clemastine to hypoxic injured mice resulted in an elevated number of myelinating OLs and improved myelin ultrastructure. Together, these findings suggest that HBOT can ameliorate the damage caused by hypoxia to white matter, and might ease some of the symptoms in neurological disorders related to white matter deficiency and hypoxia.…”

“…Myelin plays an important role in isolating the electrical information passing through an axon, which is crucial for neuronal connections [55,57]. This isolation layer is key to the proper transmission of information between neurons, as evidenced by neurological conditions that include myelination deficits [58][59][60][61][62][63].…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…It was firstly identified as one of the hit compounds with potential remyelinating capability through different high-throughput screening approaches aimed at stimulating differentiation of primary rodent OPCs and pluripotent stem cell-derived OPCs [52]. The positive effect of clemastine on remyelination was also demonstrated in vivo in the lysolecithin (LPC)-and cuprizone-induced demyelination models [52,62] and in a murine model of neonatal hypoxic injury [63,64]. Clemastine was also shown to enhance myelination in the prefrontal cortex of socially isolated mice [65].…”