Multiple sclerosis (MS) is a neurological condition marked by ongoing demyelination and neuronal damage, impacting over 3 million individuals globally. Existing MS treatments offer symptomatic relief or necessitate long-term use of immunosuppressants, often with considerable side effects. This underscores the need for alternative therapies that promote myelin regeneration. Recent studies have revealed an unexpected remyelinating potential of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), leading to renewed interest in exploring existing drugs that modulate GABA activity.

This study investigates the remyelinating effects of two FDA-approved GABA-targeting drugs: Diazepam, a positive allosteric modulator of GABAA receptors, and Valproic Acid (VPA), an antiepileptic that increases GABA bioavailability. C57BL/6 mice were fed a 0.2% cuprizone diet for four weeks to induce demyelination, followed by standard diet to promote spontaneous remyelination. These mice were then divided into groups receiving daily intraperitoneal injections of saline (control), VPA (200 mg/kg), or Diazepam (2 mg/kg) for a further four weeks. Locomotor skills were assessed using Open Field and Rotarod tests, while histological evaluations measured myelin recovery. Both VPA and Diazepam treatments improved locomotion and promoted myelin regeneration.

Real-time qPCRs revealed that both GABA-targeting drugs upregulated the expression of several myelin genes (MOG, MBP, OLIG2 and PLP1). Luxol Fast Blue staining demonstrated increased remyelination in drug-treated mice, while immunostaining for oligodendrocyte markers OLIG2 and ASPA indicated enhanced oligodendrocyte regrowth. These results emphasize the significance of targeting GABA receptors in non-neuronal cells to promote myelin repair and suggest that existing GABA-acting drugs hold promise for repurposing as treatments for MS.