GABA_B receptor agonist baclofen promotes central nervous system remyelination

Abstract

Promoting remyelination is considered as a potential neurorepair 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, a process that fails in chronic MS lesions. We previously reported that oligodendroglia express GABA B receptors (GABA B Rs) both in vitro and in vivo, and that GABA B R-mediated signaling enhances OPC differentiation and myelin protein expression in vitro. Our goal here was to evaluate the pro-remyelinating potential of GABA B R agonist baclofen (Bac), a clinically approved drug to treat spasticity in patients with MS. We first demonstrated that Bac increases myelin protein production in lysolecithin (LPC)-treated cerebellar slices. Importantly, Bac administration to adult mice following induction of demyelination by LPC injection in the spinal cord resulted in enhanced OPC differentiation and remyelination. Thus, our results suggest that Bac repurposing should be considered as a potential therapeutic strategy to stimulate remyelination in patients with MS.

Neuronal activity and remyelination: new insights into the molecular mechanisms and therapeutic advancements

“…The GABAA receptor-mediated signaling pathways obstruct myelin synthesis, their impacts on myelination may alter due to normal and pathological circumstances ( Zonouzi et al, 2015 ). GABAB receptors also play an important role in regulating myelin synthesis and remyelination, as evidenced by studies using GABAB receptor antagonists and agonists ( Pudasaini et al, 2022 ; Serrano-Regal et al, 2022 ). Furthermore, lower levels of GABA in patient brains with neurodegenerative diseases involving demyelination suggest the importance of regulating GABAergic signaling pathways for prevention ( Cawley et al, 2015 ).…”

“…OPCs express both the GABAA and GABAB receptors, which allow for GABAergic inhibitory and glutamatergic excitatory regulation ( Zonouzi et al, 2015 ). Modulation of GABA receptors and GABAergic signaling pathways is implicated in the regulation of OPCs development, myelination, and remyelination ( Bai et al, 2021 ; Serrano-Regal et al, 2022 ). In mouse cerebral slices, the presence of endogenous GABA elevated the rate of OPCs and decreased their maturation, an effect that could be nullified by the administration of gabazine, an antagonist of the GABAA receptor ( Hamilton et al, 2017 ).…”

“…Intracerebral injection of GABAB receptor antagonists in neonatal rats increased OPCs proliferation as well as decreased MBP expression and myelin production in the cingulate cortex ( Pudasaini et al, 2022 ). Baclofen, a GABAB receptor-specific agonist commonly used as a muscle relaxant in MS patients, heightened remyelination by prompting GABA to amplify Myelin-associated glycoprotein (MAG) and MBP expression levels in vitro in optic nerve explants and cerebral slices ( Serrano-Regal et al, 2022 ). Serrano-Regal and colleagues further assessed the effects of Baclofen treatment on remyelination in vivo using the LPC-triggered demyelination mouse model.…”

“…Serrano-Regal and colleagues further assessed the effects of Baclofen treatment on remyelination in vivo using the LPC-triggered demyelination mouse model. Their findings showed that such treatment encouraged the differentiation of OPCs and increased the prevalence of nascent axons in demyelinated lesions, thus indicating a beneficial impact on remyelination ( Serrano-Regal et al, 2022 ). Studies on patient brains depicting progressive demyelination with MS revealed significantly decreased GABAergic signaling pathways and reduced GABA expression in the sensorimotor cortex and hippocampus relative to normal individuals ( Cawley et al, 2015 ).…”

β-carbolines that enhance GABAA receptor response expressed in oligodendrocytes promote remyelination in an in vivo rat model of focal demyelination

“…GABAergic communication seems to be directly correlated with the degree of maturation of OLs and the myelination process ( Serrano-Regal et al, 2020 ). For example, in in vitro experiments the expression of GABA type A (GABA A ) receptors in the OL membrane is controlled by their proximity to neurons ( Arellano et al, 2016 ), whereas in in vivo experiments, potentiation of GABAergic pathways promotes myelination/remyelination of the system in a variety of experimental models and under different pharmacological conditions of modulation, including administration of tiagabine ( Zonouzi et al, 2015 ), ganaxolone ( Shaw et al, 2019 ), baclofen ( Serrano-Regal et al, 2022 ) or n-butyl-β-carboline-3-carboxylate (β-CCB; Cisneros-Mejorado et al, 2020 ). This last example represents a case of great interest because it has been shown that in in vitro experiments β-CCB acts strongly by potentiating GABA A receptor activity in OLs, with no significant effect on the receptor expressed in cortical neurons ( Arellano et al, 2016 ; Cisneros-Mejorado et al, 2020 ; Ordaz et al, 2021 ), a condition that is essential in the development of drugs with potential clinical use for myelination.…”