右美托咪定通过拟迷走神经作用促进Box 1蛋白诱导的炎症消退从而防止小鼠认知能力下降
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Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein–induced Inflammation through a Vagomimetic Action in Mice
背景
由损伤相关的分子模式引发的炎症与外科创伤和严重疾病相关的认知能力下降有牵连。我们要确定炎症的消退是否调节了右美托咪定减少损伤相关的导致认知能力下降的分子模式。
方 法
认知能力下降(由痕迹性恐惧条件反射评估)是由高分子群体box 1蛋白（一种损伤相关的分子模式）引起的，也被认为是小鼠的神经阻滞剂(迷走神经)和体液炎症反应途径。系统和神经炎症由促炎细胞因子评估。
结 果
导致认知能力下降并与损伤相关的分子模式和炎症（平均值±标准差）被右旋美托咪定消除（痕迹性恐惧条件反射:58.778.69%比41.457.64%.P<0.0001;血浆白细胞介素[IL]-1β::7.0±2.2 pg/ml比49.8±6.0 pg/ml，P<0.0001;血浆IL-6:3.2±1.6 pg/ml比19.5±1.7 pg/ml，P<0.0001;海马IL-1β:4.1±3.0 pg/mg比41.6±8.0 pmg/mg，P<0.0001;海马IL-6:3.4±1.3 pg/mg比16.2±2.7 pg/mg，P<0.0001）。右美托咪定的消炎作用被类迷走神经咪唑啉及α7乙酰胆碱受体的阻断剂阻断，而不是通过α2肾上腺素能受体。神经生长因子-1，炎症消退的协调器，是由右旋美托咪定（肺：1.5±0.1与0.7±0.1，P<0.0001）;脾：1.5±0.2比0.6±0.2，P<0.0001）上调(倍数)，导致（脂氧素-A4:1.7±0.2对0.9±0.2，P<0.0001）预消炎作用上调，以及对（白细胞介素-B4:1.0±2.0与3.0±0.3，P<0.0001）由α7乙酰胆碱受体阻断剂而阻断的促炎体液介质下调.
结 论
右美托咪定能通过类迷走神经（神经的）和体液途径消除炎症，从而防止与损伤相关的分子模式介导的认知能力下降。
原始文献摘要
Background: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine- induced reduction of damage-associated molecular pattern induced cognitive decline.
Methods: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines.
Results: Damage-associated molecular pattern induced cognitive decline and inflammation (mean SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 8.69% vs. 41.45 7.64%, P < 0.0001; plasma interleukin [IL]-1β: 7.0 2.2 pg/ml vs. 49.8 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 1.6 pg/ml vs. 19.5 1.7 pg/ml, P < 0.0001; hippocampal IL-1β: 4.1 3.0 pg/mg vs. 41.6 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 1.3 pg/mg vs. 16.2 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 0.1 vs. 0.7 0.1, P < 0.0001; spleen: 1.5 0.2 vs. 0.6 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 0.2 vs. 0.9 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 0.2 vs. 3.0 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade.
Conclusions: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern mediated cognitive decline.
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