Dexmedetomidine attenuates pyohemia-associated delirium in mice through the cholinergic anti-inflammatory pathway

Abstract

Objective To study if the protective effect of dexmedetomidine on the pyohemia-associated delirium is through the cholinergic anti-inflammatory pathway. Methods Sixty male adult C57 mice were randomly divided into five groups (n=12 each): saline group (group C), dexmedetomidine (DEX) alone group (group DEX), endotoxemia (LPS) group (group LPS), dexmedetomidine protection group (group LPS+ DEX) and alpha-bungarotoxin (α-BGT) group (group α-BGT). Each group were assigned to two subunits (n=6 each), mice in subunit one were sacrificed after examining the open field test, mice in subunit two were sacrificed after testing the novel object recognition. The level of inflammatory factors were measured by enzyme-linked immune sorbent assay (ELISA). The ultrastructure changes of the hippocampus in mice were observed by transmission electron microscopy. Results Compared with group C, there are no significant differences in group DEX. Dexmedetomidine significantly attenuated the delirious syndrome after LPS induced endotoxemia, however, the effect of dexmedetomidine disappeared in group α-BGT, and the syndrome of cognitive dysfunction in LPS group were more severe than that in group α-BGT. (1) The open field test show that there are no significant differences each group with that before model establishment; after the models were established 24 h, compared with group C, group LPS show that the abilities of cognition to new environment、learning and memory were decreasing, the tension is increasing. preemptive administration of dexmedetomidine significantly attenuated the delirious syndrome after LPS induced endotoxemia; however, preemptive administration of dexmedetomidine failed to control the delirious syndrome in group α-BGT. (2) The novel object recognition testshow that compared to group C, the ability of exploring the novel object is decreasing; preemptive administration of dexmedetomidine significantly improve the exploration ability, however, preemptive administration of dexmedetomidine failed to control the delirious syndrome in group α-BGT. (3) The results of ELISA show that: Compared with group C, the concentrations of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in serum and Hippocampus were all increased in LPS groups[Serum (ng/L) TNF-α: 794.80±93.99 vs. 23.60±3.03, IL-1β: 148.49±24.80 vs. 64.55±5.13, Hippocampus (pg/mg·prot) TNF-α: 176.14±11.25 vs. 6.71±0.49, IL-1β: 50.61±5.86 vs. 16.73±1.15, P=0.000], compared with group LPS, the concentrations were all significantly decreased in group LPS+ DEX[Serum (ng/L) TNF-α: 184.44±26.58 vs. 794.80±93.99, IL-1β: 77.43±10.75 vs. 148.49±24.80, Hippocampus (pg/mg·prot) TNF-α: 64.83±13.09 vs. 176.14±11.25, IL-1β: 17.97±2.26 vs. 50.61±5.86, P=0.000]. However, α-BGT can reverse the protective effect[Serum (ng/L): TNF-α: 812.31±86.25 vs. 184.44±26.58, IL-1β: 156.42±17.94 vs. 77.43±10.75, Hippocampus (pg/mg·prot) TNF-α: 181.94±8.69 vs. 64.83±13.09, IL-1β: 52.10±5.59 vs. 17.97±2.26, P=0.000]. TEM shown that the histopathological damage of hippocampus tissue in group LPS and α-BGT were heavier, which in group LPS+ DEX was reversed partially. Conclusion Central alpha-2 agonist dexmedetomidine attenuates sepsis-associated delirium syndrome likely through activating cholinergic anti-inflammatory pathway and inhibiting the inflammatory responses in serum and brain. Key words: Delirium; Dexmedetomidine; Endotoxemia; Cholinergic anti-inflammatory pathway; Inflammatory response