Centrally administered orexin prevents lipopolysaccharide and colchicine induced lethality via the vagal cholinergic pathway in a sepsis model in rats
Centrally administered orexin prevents lipopolysaccharide and colchicine induced lethality via the vagal cholinergic pathway in a sepsis model in rats
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在大鼠脓毒症模型中，集中施用食欲素可防止脂多糖和秋水仙碱通过迷走神经胆碱能途径诱导的致死作用
DOI：
10.1016/j.bcp.2020.114262
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发表时间：
2020
影响因子：
5.8
通讯作者：
Okumura Toshikatsu
中科院分区：
文献类型：
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作者：
Igarashi Sho;Nozu Tsukasa;Ishioh Masatomo;Kumei Shima;Saito Takeshi;Toki Yasumichi;Hatayama Mayumi;Yamamoto Masayo;Shindo Motohiro;Tanabe Hiroki;Okumura Toshikatsu
食欲素是参与多种生理功能的神经肽。越来越多的研究结果表明食欲素与败血症之间存在联系。最近的一项研究表明，食欲素的作用集中，以改善脓毒症的条件。本研究旨在阐明中枢增食欲素对脓毒症的保护作用的确切机制。我们建立了一个新的脓毒症模型，通过治疗大鼠与脂多糖（LPS）和秋水仙碱，并使用此来检查脑食欲素对生存的影响。在化学品注射后三天或死亡时停止观察存活情况。通过皮下注射1 mg/kg LPS和1 mg/kg秋水仙碱的组合建立致死模型（大鼠在24 h内死亡）。Toll样受体4（TLR 4）抑制剂完全阻断了致死性，这表明LPS-TLR 4信号传导在此过程中起着至关重要的作用。脑池内食欲素-A剂量依赖性地降低脓毒症模型中的致死率，而脑池内食欲素-B或腹膜内食欲素-A均不改变死亡率。用卡巴胆碱或2-脱氧-D-葡萄糖刺激迷走神经可提高存活率，阿托品可有效阻断卡巴胆碱或2-脱氧-D-葡萄糖的保护作用。食欲素-A诱导的死亡率降低显着阻断阿托品或手术迷走神经切断术。脑池内注射OX 1受体拮抗剂阻断了脑池内注射食欲素A、卡巴胆碱或2-脱氧-D-葡萄糖对生存率的改善。这些结果表明食欲素在我们的脓毒症模型治疗（LPS和秋水仙素）中起中枢作用以降低致死率。迷走神经胆碱能通路的激活可能介导食欲素的作用，脑中的OX 1受体可能在此过程中发挥作用。由于传出迷走神经介导的抗炎机制，我们推测，迷走胆碱能抗炎通路是牵连在败血症致死率降低脑食欲素的机制。
Orexins are neuropeptides implicated in several physiological functions. Accumulating findings suggest a relationship between orexin and sepsis. A recent study demonstrated that orexin acts centrally to improve conditions in sepsis. The present study aims to clarify the precise mechanisms by which central orexin could induce a protective action against septic conditions. We established a new septic model by treating rats with lipopolysaccharide (LPS) and colchicine and used this to examine the effect of brain orexin on survival. Observation of survival was stopped three days after the chemicals injection or at death. We established a lethal model (rats died within 24 h) by injecting subcutaneously a combination of 1 mg/kg LPS and 1 mg/kg colchicine. A Toll-like receptor 4 (TLR4) inhibitor completely blocked lethality, suggesting a vital role of LPS-TLR4 signaling in the process. Intracisternal orexin-A dose-dependently reduced lethality in the sepsis model while neither intracisternal orexin-B nor intraperitoneal orexin-A changed the mortality rate. Vagal stimulation with carbachol or 2-deoxy-D-glucose improved survival and atropine potently blocked the protection by carbachol or 2-deoxy-D-glucose. The orexin-A-induced reduction of lethality was significantly blocked by atropine or surgical vagotomy. Intracisternal injection of an OX1receptor antagonist blocked the improvement of survival by intracisternal injection of orexin-A, carbachol, or 2-deoxy-D-glucose. These results suggest that orexin acts centrally to reduce the lethality in our septic model treated (LPS and colchicine). Activation of the vagal cholinergic pathway may mediate the action of orexin, and the OX1receptor in the brain might play a role in the process. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the mechanisms of septic lethality reduction by brain orexin.