GABA_BR 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.

GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes

“…For that reason, the search for drugs that protect oligodendrocytes from this damage will provide novel agents to treat WM injury in the CNS. GABA B and GABA A R agonists have been described as displaying neuroprotective roles ( Tu et al, 2010 ; Wei et al, 2012 ; Hleihil et al, 2021 ), and recent reports have outlined their importance in oligodendrocyte functionality, proliferation, differentiation and remyelination ( Zonouzi et al, 2015 ; Kalakh and Mouihate, 2019 ; Serrano-Regal et a., 2020a ; Serrano-Regal et al, 2020b ; Bai et al, 2021 ; Serrano-Regal et al, 2022 ). Here, we demonstrate that baclofen and muscimol, GABA B and GABA A R agonists, respectively, exert a protective role in the oligodendrocyte response to glutamate-induced excitotoxicity, by alleviating the damage caused by this insult enhancing the presence of calcium-impermeable GluR2 subunits on the oligodendroglial cell surface.…”

“…Oligodendrocytes express the two main GABA receptors (GABAR), ionotropic GABA A R and metabotropic GABA B R ( Serrano-Regal et al, 2020 ), and the relevance of GABARs for oligodendrocyte functionality has become clear in recent years (reviewed in Serrano-Regal et al, 2020 ; Bai et al, 2021 ). GABARs are related to myelination and neuroprotection in the CNS, given the link between GABA A R signaling disruption or downregulation and reduced myelination observed in vivo ( Zonouzi et al, 2015 ; Kalakh and Mouihate, 2019 ), or the decreased myelination following GABA A R activation observed in organotypic slices ( Hamilton et al, 2017 ), and considering the remyelinating capacity of GABA B R agonist baclofen following spinal cord injury ( Serrano-Regal et al, 2022 ).…”