Sepsis-associated encephalopathy (SAE) is a significant clinical issue that is associated with increased mortality and cost of health care. Dexmedetomidine, an α2 adrenoceptor agonist that is used to provide sedation, has been shown to induce neuroprotection under various conditions. This study was designed to determine whether dexmedetomidine protects against SAE and whether α2 adrenoceptor plays a role in this protection. Six- to eight-week old CD-1 male mice were subjected to cecal ligation and puncture (CLP). They were treated with intraperitoneal injection of dexmedetomidine in the presence or absence of α2 adrenoceptor antagonists, atipamezole or yohimbine, or an α2A adrenoceptor antagonist, BRL-44408. Hippocampus and blood were harvested for measuring cytokines. Mice were subjected to Barnes maze and fear conditioning 14 days after CLP to evaluate their learning and memory. CLP significantly increased the proinflammatory cytokines including tumor necrosis factor α, interleukin (IL)-6 and IL-1β in the blood and hippocampus. CLP also increased the permeability of blood-brain barrier (BBB) and impaired learning and memory. These CLP detrimental effects were attenuated by dexmedetomidine. Intracerebroventricular application of atipamezole, yohimbine or BRL-44408 blocked the protection of dexmedetomidine on the brain but not on the systemic inflammation. Astrocytes but not microglia expressed α2A adrenoceptors. Microglial depletion did not abolish the protective effects of dexmedetomidine. These results suggest that dexmedetomidine reduces systemic inflammation, neuroinflammation, injury of BBB and cognitive dysfunction in septic mice. The protective effects of dexmedetomidine on the brain may be mediated by α2A adrenoceptors in the astrocytes.

中文翻译：

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右美托咪定通过中枢 α2A 肾上腺素能受体减轻脓毒症相关炎症和脑病

脓毒症相关脑病 (SAE) 是一个重要的临床问题，与死亡率和医疗保健成本的增加有关。右美托咪定是一种用于提供镇静作用的 α2 肾上腺素能受体激动剂，已显示在各种条件下诱导神经保护作用。本研究旨在确定右美托咪定是否对 SAE 有保护作用，以及 α2 肾上腺素能受体是否在这种保护作用中起作用。六到八周大的 CD-1 雄性小鼠接受盲肠结扎和穿刺 (CLP)。在存在或不存在 α2 肾上腺素受体拮抗剂阿替美唑或育亨宾或 α2A 肾上腺素受体拮抗剂 BRL-44408 的情况下，腹腔注射右美托咪定对他们进行治疗。收集海马和血液用于测量细胞因子。在 CLP 后 14 天对小鼠进行巴恩斯迷宫和恐惧条件反射，以评估它们的学习和记忆。CLP 显着增加血液和海马中的促炎细胞因子，包括肿瘤坏死因子 α、白细胞介素 (IL)-6 和 IL-1β。CLP 还增加了血脑屏障 (BBB) 的通透性并损害了学习和记忆。这些 CLP 不利影响被右美托咪定减弱。阿替美唑、育亨宾或 BRL-44408 的脑室内应用阻断了右美托咪定对大脑的保护，但不阻断对全身炎症的保护。星形胶质细胞而非小胶质细胞表达α2A 肾上腺素能受体。小胶质细胞耗竭并没有消除右美托咪定的保护作用。这些结果表明右美托咪定可减少全身炎症、神经炎症、败血症小鼠 BBB 损伤和认知功能障碍。右美托咪定对大脑的保护作用可能是由星形胶质细胞中的α2A 肾上腺素能受体介导的。