Chara, J. C. | bioRxiv Science

bioRxiv2022

GABABR agonist baclofen promotes central nervous system remyelination

Promoting remyelination - the endogenous response by which lost myelin sheaths are regenerated - is considered as a potential neuroprotective strategy to prevent/limit the development of permanent neurological disability in patients with multiple sclerosis (MS). To this end, a number of clinical trials are investigating the potential of existing drugs to enhance oligodendrocyte progenitor cell (OPC) differentiation, the process that fails in chronic MS lesions. As we previously reported that oligodendroglia lineage cells express GABAB receptors (GABABRs) both in vitro and in vivo, and that GABABR-mediated signaling enhances OPC differentiation and myelination in vitro, here we focused on the remyelinating potential of the best-known GABABR agonist baclofen (Bac), already approved to treat spasticity in MS. We demonstrated that Bac increases myelin protein production following lysolecithin (LPC)-induced demyelination in cerebellar ex vivo slices. In addition, Bac administration enhanced OPC differentiation and remyelination in LPC-induced spinal cord lesions in adult mice. Thus, our results suggest that Bac should be considered as a potential therapeutic agent, not only to treat spasticity, but also to improve remyelination in patients with MS.

neuroscience↗

bioRxiv2021

Clemastine induces an impairment in developmental myelination

Abnormalities in myelination are associated to behavioral and cognitive dysfunction in neurodevelopmental psychiatric disorders. Thus, therapies to promote or accelerate myelination could potentially ameliorate symptoms in autism. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, is the most promising drug with promyelinating properties (Mei et al., 2014). Clemastine penetrates the blood brain barrier efficiently and promotes remyelination in different animal models of neurodegeneration including multiple sclerosis, ischemia and Alzheimers disease. However, its role in myelination during development is unknown. We showed that clemastine treatment during development increase oligodendrocyte differentiation in both white and gray matter. However, despite the increase in the number of oligodendrocytes, conduction velocity of myelinated fibers of corpus callosum decreased in clemastine treated mice. Confocal and electron microscopy showed a reduction in the number of myelinated axons and nodes of Ranvier and a reduction of myelin thickness in corpus callosum. To understand the mechanisms leading to myelin formation impairment in the presence of an excess of myelinating oligodendrocytes, we focused on microglial cells which also express muscarinic M1 receptors. Importantly, the population of CD11c+microglia cells, necessary for myelination, as well as the levels of insulin growth factor-1 decrease in clemastine-treated mice. Altogether, these data suggest that clemastine impact on myelin development is more complex than previously thought and could be dependent on microglia-oligodendrocyte crosstalk. Further studies are needed to clarify the role of microglia cells on developmental myelination.

neuroscience↗