Dexmedetomidine Controls Systemic Cytokine Levels Through The Cholinergic Anti-inflammatory Pathway

Objective Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation, butthe mechanism is not clear. This study intends to elucidate the anti-inflammatory mechanism of dexmedetomidinethrough the cholinergic anti-inflammatory pathway.Methods The BALB/c mice were used to investigate the therapeutic potential of dexmedetomidine in a murine model of endotoxemia induced by endotoxin. Animals were assigned to one of four protocols. Protocol one:animals were randomly assigned to control group, dexmedetomidine group and sterile saline group (n=20each), and these animals were used for survival analysis.The survival rate was assessed up to120h after endotoxin injection. Protocol two:animalswere randomly assigned to one of four groups (n=16each):group1(group Saline), treated with sterile saline15min prior to endotoxin treatment (10mg·kg-1over2min); group2(group Dex), treated with dexmedetomidine15min prior to endotoxin treatment; group3(group aBGT+Dex), treated with a7nicotinic acetylcholine receptors (a7nAChR) antagonist alpha-bungarotoxin (? BGT,1?g/kg)15min prior to dexmedetomidine treatment; group4(group Saline+Dex), treated with equivalent sterile saline15min prior to dexmedetomidine treatment; group5(group C), treated with equivalent sterile saline only. Protocol three:animals were randomly assigned to one of two groups (n=16each): vagotomy group (group VNX+Dex), right cervical vagus nerve was exposed and transected; sham-operated group (group SHAM+Dex), the cervical vagus nerve was visualized, but was neither isolated from the surrounding tissues nor transected. Protocol four:animals were treated with dexmedetomidine(40?g/kg) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system(n=16each).Results In the survival analysis groups, the survival rate of dexmedetomidine group was significantly higher than endotoxemia group (65%versus25%, P<0.01). Pre-emptive administration of dexmedetomidine significantly attenuated the cytokine response after endotoxin induced endotoxemia(TNF-alpha, IL-lbeta, IL-6, P<0.01, respectively). However, the systemic cytokine levels in group ?BGT+Dex was significant higher in comparison with group Saline+Dex(TNF-alpha, IL-lbeta, IL-6, P<0.01, respectively). And the similar results was also found in group VNX+Dex compared to the group SHAM+Dex. Furthermore, pre-emptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment(P<0.01).Conclusions The results of this research demonstrate that the pre-emptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release. However, administration of dexmedetomidine to vagotomy or a7nAChR antagonist pretreatment mice failed to suppress TNF levels, indicating that the vagus nerve and ?1nAChR mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine. These findings show that central alpha-2agonist dexmedetomidine suppresses systemic inflammation through vagal-and ?7nAChR-dependent mechanism.