Attenuation Of Neuroinflammation By Dexmedetomidine Is Associated With Activation Of A Cholinergic Anti-inflammatory Pathway In A Rat Tibial Fracture Model

Background:Sustained neuroinflammation contributes to the pathogenesis ofpostoperative cognitive dysfunction. Dexmedetomidine, a selective α-2adrenergicreceptor agonist, exhibits a protective role in the brain. This study investigatedwhether dexmedetomidine pretreatment attenuates neuroinflammation induced bytibial fracture in rats, as well as the mechanism by which dexmedetomidine providesits neuroprotection.Methods:Animals were assigned to one of several groups in two protocols(n = 5 in each group). Protocol 1: Group C(sham), Group S(tibial fracture), Group DS(dexmedetomidine pretreatment + tibial fracture), Group VDS(vagotomy +dexmedetomidine + tibial fracture), and group VS(vagotomy + tibial fracture); Protocol 2:Group C(saline), Group S(tibial fracture), Group DS(dexmedetomidine pretreatment +tibial fracture), Group MDS(methyllycaconitine + dexmedetomidine + tibial fracture), and Group MS(methyllycaconitine + tibial fracture). Methyllycaconitine is an α-7 nicotinic acetylcholine receptor(α7nAChR) antagonist. At 24 h after trauma, proinflammatory cytokines in the hippocampus, including tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β), were assessed using an enzyme-linked immunosorbent assay.Levels of nuclear factor-kappa B(NF-κB), and microglial(CD11b) and astrocytic(GFAP)responses to injury in the hippocampus were visualized by immunofluorescence and Western blot.Results: Tibial fracture significantly increased the levels of TNF-α and IL-1β and the expression of NF-κB in the hippocampus(P < 0.05). Overexpression of microglial and astrocytic responses to injury were observed in the hippocampus(P < 0.05).Dexmedetomidine pretreatment significantly suppressed the inflammatory responses, as evidenced by lower TNF-α and IL-1β levels(P < 0.05), significantly inhibited NF-κB activity, and alleviated overexpression of microglia and astrocytes in the hippocampus(P <0.05). However, pretreatment with dexmedetomidine failed to attenuate cytokine responses(NF-κB) and microglial and astrocytic activity in the VDS and MDS groups.Conclusion: These results suggest that the intact vagus nerve and α7nAChR mediated cholinergic anti-inflammatory pathway is essential for theanti-inflammatory effects of dexmedetomidine. Pretreatment with dexmedetomidineattenuates neuroinflammation caused by tibial fracture in rats throughvagal-dependent and α7nAChR-dependent mechanisms.