The potential of repurposing clemastine to promote remyelination

Abstract

White matter in the central nervous system comprises bundled nerve fibers myelinated by oligodendrocytes. White matter injury, characterized by the loss of oligodendrocytes and myelin, is common after ischemic brain injury, inflammatory demyelinating diseases including multiple sclerosis, and traumatic damage such as spinal cord injury. Currently, no therapies have been confirmed to promote remyelination in these diseases. Over the past decade, various reports have suggested that the anti-muscarinic drug clemastine can stimulate remyelination by oligodendrocytes. Consequently, the repurposing of clemastine as a potential treatment for a variety of neurological disorders has gained significant attention. The therapeutic effects of clemastine have been demonstrated in various animal models, and its mechanisms of action in various neurological disorders are currently being investigated. In this review, we summarize reports relating to clemastine administration for white matter injury and neurological disease and discuss the therapeutic potential of remyelination promotion.

Keywords: clemastine; drug repositioning; oligodendrocyte; remyelination; white matter injury.

Figure 1

Therapeutic effects of clemastine in a mouse model of white matter injury and molecular mechanisms of action in oligodendrocyte precursor cells. (A) The animal models of white matter injury are induced demyelination, oligodendrocyte loss, motor paralysis and sensory paralysis. Motor function and remyelination state of oligodendrocytes (OLs) are assessed by behavioral tests and histological analysis. Clemastine administration in these animal models promotes remyelination and functional recovery. (B) Clemastine administration activates the extracellular signal-regulated kinase (ERK) pathway to promote differentiation via inhibition of the M1 muscarinic acetylcholine receptor (CHRM1) in oligodendrocyte precursor cells (OPCs). Clemastine also induces the activation of H3K9 histone methyltransferases and the glutathione S-transferase 4α (Gsta4)/4-hydroxynonenal (4-HNE) pathway in OPCs. In addition, clemastine promotes the N-methyl-d-aspartate (NMDA) receptor-rich state in OPCs. Shown are the schematic diagram of oligodendrocyte (OL) differentiation and stage-specific markers.