气体信号分子硫化氢调控内源性甲醛拮抗术后认知功能障碍

To explore the pathogenesis mechanism and the prevention and treatment methods of postoperative cognitive dysfunction (POCD) from a new perspective is a focus in anesthesiology and neuroscience. Based on the literature and our previous studies, we propose a scientific hypothesis that H2S prevents POCD by regulation of endogenous formaldehyde ". After establishment of the animal models of POCD under anesthesia and surgical stress, we will elucidate the anti-POCD role of H2S from the damage of brain, nerve inflammation and cognitive behavioral, clear that endogenous formaldehyde participates in the formation of POCD by exploring the changs of brain-derived formaldehyde content and its important metabolic enzyme (SSAO, ADH-3 and ALDH-2) expression levels induced by anesthesia and surgical stress and investigating the effects of changes in the level of endogenous formaldehyde on the formation of POCD, and clarify that H2S prevents POCD by regulation of endogenous formaldehyde through investigating the effects of H2S on the increase of endogenous generation of formaldehyde and the changes in SSAO, ADH-3 and ALDH-2 expressions induced by anesthesia and surgical stress. Carrying out the project, we will obtain a new breakthrough to prevent and treat POCD from the new perspective of endogenous H2S, reveal the pathophysiological mechanisms of POCD and the the mechanism underlying the anti-POCD role of H2S from the new perspective of endogenous formaldehyde, and provide new targets and new clues for prevention and treatment of POCD.

从新的视角探讨术后认知功能障碍(POCD)的发病机制、寻找新的防治手段是备受关注的课题。基于文献和前期研究，提出“H2S调控内源性甲醛拮抗POCD”的科学假说。为此，本项目在麻醉和手术应激的POCD动物模型上，从脑组织损伤、神经炎症反应和认知行为学等方面深入阐明H2S的抗POCD作用；观察术后脑组织内源性甲醛含量及其重要代谢酶 (SSAO、ADH-3 和 ALDH-2) 表达水平的改变，探讨改变内源性甲醛水平对POCD的影响，以明确内源性甲醛参与了POCD的形成；探讨H2S对麻醉和手术应激促进内源性甲醛生成及SSAO、ADH-3 和 ALDH-2表达的影响，以明确H2S可通过调控内源性甲醛的生成而拮抗POCD。本项目的开展，将从内源性H2S发掘防治POCD的新突破口、从内源性甲醛这一新视角揭示POCD的病理生理机制和H2S抗POCD的作用机理，为POCD的防治提供新靶点和新线索。

手术后的老年患者往往会出现认知功能障碍，它会造成机体海马组织内氧化应激和凋亡增加，降低海马组织的神经发生能力。基于大鼠海马组织的内质网应激及神经炎症参与了学习记忆与认知功能障碍，而硫化氢 (Hydrogen sulfide, H2S) 对学习记忆具有调节作用以及在中枢神经系统疾病中具有神经保护作用。本研究拟探讨H2S抗老年大鼠术后认知功能障碍的机制以及对术后老年大鼠海马组织的氧化应激、凋亡及神经发生的影响。因此，使用18-20月龄的老年大鼠用异氟烷麻醉后行进行剖腹探查手术，术后3天进行行为学Y迷宫、新物体识别和Morris水迷宫试验的检测，结果显示：术后老年大鼠Y迷宫试验中的交替正确率显著降低；在新异物体识别试验中的新物体识别指数明显下降；同时术后老年大鼠海马组织内H2S的生产能力及H2S生成酶CBS和3-MST的表达下降，内质网应激相关蛋白(Bip和Cleaved caspase-12)的表达水平升高，促炎因子(IL-1β 、 IL-6 和 TNF-α)的含量和CD45+细胞及IBA-1+细胞数量显著增多，提示术后老年大鼠的认知功能障碍与海马内源性硫化氢的生成紊乱、内质网应激及神经炎症反应的增强有关。给予老年大鼠 NaHS (30 or 100 μmol/kg/d, i.p.) 预处理 2 w，可以显著逆转术后引起的老年大鼠认知功能障碍。同时发现NaHS (100 μmol/kg) 明显减少术后大鼠海马组织中MDA和4-HNE的含量并且增加了术后老年大鼠海马组织中GSH的含量和SOD的活力。以上结果表明，H2S可以通过抑制海马内质网应激及神经炎症改善老年大鼠术后认知功能障碍，减轻术后老年大鼠海马组织的氧化应激水平和凋亡的发生以及提高海马组织神经发生能力。