Dexmedetomidine pretreatment improves postsurgical delay in neurocognitive recovery in aged mice by inhibiting hippocampal microglial activation via activation of cholinergic anti-inflammatory pathways.

BACKGROUND: Perioperative use of dexmedetomidine (DEX) reduces the incidence of Delayed Neurocognitive Recovery (DNR) in elderly patients, though mechanisms remain unclear. This study investigated whether DEX improves DNR by inhibiting microglial activation and explored the cholinergic anti-inflammatory pathway's role. METHODS: An exploratory laparotomy model was established in aged C57BL/6J mice, with preoperative treatment using DEX or DEX combined with α-bungarotoxin. Cognitive function was assessed through the novel object recognition (NOR) and Morris water maze (MWM) tests, while immunofluorescence was used to observe microglial morphology, and qPCR and ELISA were employed to detect inflammatory factor expression. RESULTS: DEX pretreatment significantly reduced the escape latency of aged mice on postoperative days 3-5 (50.50 ± 3.73 vs. 55.01 ± 4.01, P = 0.04; 36.36 ± 4.31 vs. 43.42 ± 5.64, P = 0.01; 27.00 ± 3.94 vs. 34.50 ± 5.54, P = 0.006), increased number of times crossing the previous platform location (2.50 ± 1.31 vs. 1.08 ± 0.90, P = 0.02), and percentage of dwell time in the target quadrant (37.87 ± 9.66 vs. 25.00 ± 4.48, P < 0.001). DEX pretreatment also reduced the expression of pro-inflammatory cytokines in the hippocampus (TNF-α, 604.10 ± 165.40 vs. 915.30 ± 97.64, P = 0.002; IL-6, 145.30 ± 12.11 vs. 176.50 ± 16.15, P = 0.002; IL-1β, 59.68 ± 4.29 vs. 68.73 ± 3.11, P = 0.001) of aged mice postoperatively, as well as in the spleen and serum. Additionally, DEX pretreatment reduces microglia count (96.60 ± 11.84 vs. 136.20 ± 32.62, P = 0.05), fluorescence (0.96 ± 0.06 vs. 1.10 ± 0.02, P < 0.001), morphology (7.20 ± 2.17 vs.12.80 ± 2.28, P = 0.002) in aged mice post-surgery. Pre-administration of α-bungarotoxin before DEX pretreatment partially reversed these effects. CONCLUSIONS: DEX pretreatment ameliorated DNR in aged mice is related to inhibition of microglial activation, which was at least partially attributed to activation of the cholinergic anti-inflammatory pathway.