The anti-spasticity drug baclofen alleviates collagen-induced arthritis and regulates dendritic cells

Abstract

Baclofen is used clinically as a drug that treats spasticity, which is a syndrome characterized by excessive contraction of the muscles and hyperflexia in the central nervous system (CNS), by activating GABA(B) receptors (GABA(B)Rs). Baclofen was recently reported to desensitize chemokine receptors and to suppress inflammation through the activation of GABA(B)Rs. GABA(B)Rs are expressed in various immune cells, but the functions of these receptors in autoimmune diseases remain largely unknown. In this study, we investigated the effects of baclofen in murine collagen-induced arthritis (CIA). Oral administration of baclofen alleviated the clinical development of CIA, with a reduced number of IL-17-producing T helper 17 (T(H)17) cells. In addition, baclofen treatment suppressed dendritic cell (DC)-primed T(H)17 cell differentiation by reducing the production of IL-6 by DCs in vitro. Furthermore, the pharmacological and genetic blockade of GABA(B)Rs in DCs weakened the effects of baclofen, indicating that GABA(B)Rs are the molecular targets of baclofen on DCs. Thus, our findings revealed a potential role for baclofen in the treatment of CIA, as well as a previously unknown signaling pathway that regulates DC function.

Immunological GABAergic interactions and therapeutic applications in autoimmune diseases

“…Recently, Huang et al [62] demonstrated that baclofen (GABA B R agonist) alleviates CIA. Oral administration of baclofen decreased Th17 cell numbers, and suppressed IL-6 production by DCs.…”

A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells

“…GABA-R activation has been shown to inhibit or reverse disease in animal models of type 1 diabetes (T1D) [4, 6, 9, 12–14], rheumatoid arthritis [15], and experimental autoimmune encephalomyelitis [16, 17] and to limit inflammation and disease in type 2 diabetes models [18–20]. Studies of GABA's protective mechanisms in these disease models revealed that GABA inhibits inflammatory Th1, Th17, and CD8 + responses [4, 6, 9, 13–15], as well as antigen-presenting cell function and TNF α production [16, 21, 22]. Thus, GABA-R activation can inhibit inflammation caused by different mechanisms in mice with different genetic backgrounds.…”

GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19

“…Histopathological analysis of lungs from mice that received GABA just after MHV-1 inoculation revealed that three days post-infection these mice had significantly reduced lung inflammation and markers of lung damage relative to that in control mice. There are a number of different biological processes through which GABA treatment may have ameliorated the severity of pneumonitis: 1) GABA can inhibit macrophage and dendritic cell inflammatory activities (1–3, 29, 46, 47). Likewise, GABA A -R PAMs reduce the numbers of macrophages in broncholavage fluid, lung secretion of inflammatory cytokines, and inflammatory responses by rodent and human macrophages (22, 27–31).…”