GABABR agonist baclofen promotes central nervous system remyelination

Abstract

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.