Abstract
Many studies showed that dopamine receptors (DRs) agonists have anti-inflammatory effects. Rotigotine, a non-ergot dopamine receptor agonist, mainly actives DRD2/DRD3/DRD1. Rotigotine extended-release microspheres (RoMS) are a sustained-release formulation that can release sustainably rotigotine for more than 7 days after a single dose of RoMS. This study aimed to investigate whether RoMS can attenuate the lipopolysaccharide (LPS)-induced liver injury of mice. The liver injury was evaluated by assaying serum transaminase and observing histopathological changes. The levels of pro-inflammatory cytokines in serum were also detected. Western blot was employed to assay the expression of proteins in the Akt/NF-κB pathway. The results showed that pre-administration with a single dose of RoMS could inhibit the increase of serum transaminase induced by LPS, alleviate the pathological damage of liver tissue, and decrease the levels of tumor necrosis factor-α and interleukin-6. In addition, RoMS decreased Toll-like receptor 4 protein expression in liver tissue. RoMS mitigated liver injury by activating DRs and negatively regulating the β-arrestin2-dependent Akt/NF-κB signaling pathway. The effects of RoMS could be weakened or abolished by the specific DRD2 antagonist, R121. In conclusion, activation of DRs inhibited the releases of pro-inflammatory cytokines and alleviated the immune-mediated liver injury induced by LPS in mice. The anti-inflammatory mechanism of RoMS may be related to the regulation of the β-arrestin2-dependent Akt/NF-κB signaling pathway.
Highlights
The liver is an important organ mediating metabolism and immunity
Rotigotine is a non-ergot dopamine receptor agonist that mainly acts on DRD2/DRD3/DRD1
R121 abrogated partially the effects of RoMS on the activities of AST and ALT. These results suggest that RoMS can attenuate immune-mediated liver injury
Summary
The liver is an important organ mediating metabolism and immunity. It plays an important role in the phagocytosis of bacteria and pathogens (Jeschke et al, 2007; Jeschke, 2009). When the immune response is excessive, liver immune cells will continue to produce harmful substances such as inflammatory factors, inducing immune-related liver injury. LPS enters the liver through blood circulation and binds to TLR4 on the surface of hepatic macrophages, which in turn can activate the nuclear factor-κB (NF-κB) pathway (Martinon et al, 2009; Wu et al, 2020) This process promotes the production of inflammatory cytokines, chemokines, and inducible nitric oxide synthase, inducing hepatocyte necrosis or apoptosis and accelerating liver injury (Zi et al, 2019). The activated signaling pathways results in an excessive production of inflammatory mediators and the formation of inflammatory factor storms that exacerbates the immune response to LPS-induced liver injury. This study aimed to investigate the effects and potential mechanisms associated with continuous DRs activation on immune-mediated liver injury
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