Background: Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system characterized by demyelination and axonal damage. This chronic neurological disorder affects millions worldwide and poses a significant economic and social burden. Current therapeutic strategies for MS primarily focus on mitigating neuroinflammation but do not effectively reverse demyelination. The GABA_B receptor is expressed in oligodendrocytes and immune cells. GABA_B receptors appear to play a role in modulating immune cells and promoting remyelination of damaged neurons. However, the effects of GABA_B-receptor modulation in animal models of MS remain largely unexplored. Therefore, this study evaluates the therapeutic role of GABA_B receptor activity in rats with experimental autoimmune encephalomyelitis (EAE) to mimic MS in humans. Methods: EAE was induced in rats by immunization with 200 μg myelin oligodendrocyte glycoprotein (35-55) peptide in complete Freund’s adjuvant containing killed Mycobacterium tuberculosis. Additionally, rats received injections of 200 ng pertussis toxin on the day of immunization and 48 h later. The EAE rats were treated with normal saline, CGP-55845, baclofen, or CGP-55845 + baclofen, i.p. Myelination in the lumbar spinal cord was assessed in control rats at 18- and 35-day postinduction. Results: CGP treatment significantly enhanced remyelination in EAE rats. This was evidenced by significant improvements in body weight and EAE clinical scores, as well as favorable histological changes. The observed increase in myelin expression in CGP-treated animals suggests that CGP-55845 promotes both remyelination and oligodendrocyte differentiation. Conclusions: Our results suggested that the selective GABA_B receptor antagonist CGP-55845 plays a significant role in promoting neural stem cell proliferation, particularly oligodendrocyte cells and remyelination in the EAE model of MS

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