【作者】 赵悦；

【导师】 左萍萍； 刘雁勇； 杨楠；

【作者基本信息】 中国协和医科大学 ， 药理学， 2010， 硕士

【摘要】 术后精神障碍(postoperative mental disorder, POMD)是老龄患者术后常见的一种急性精神错乱状态,临床基本特征为意识、注意力、认知和知觉障碍。其发病原因机制较复杂,包括围术期多种因素。临床研究表明高龄和术前抗胆碱药的使用可能是其重要原因之一。本研究旨在观察老龄大鼠基础认知水平的变化及抗胆碱药阿托品在临床剂量(0.06mg/kg)下对其记忆和精神状态的影响,并初步探讨其机制。我们采用水迷宫实验和Y迷宫实验测试老龄大鼠记忆能力的变化及给予阿托品后不同时间点(1天、4天、7天)其记忆能力的变化；采用开场和十字高架迷宫实验观察老龄大鼠精神状态的变化及给予阿托品后对其造成的影响。结果表明,自然衰老大鼠的记忆能力存在下降趋势,而临床常用剂量下的阿托品对衰老大鼠的学习记忆功能没有明显影响,但对其精神状态产生了影响,有一定的双向波动性及个体差异性。进一步研究其机制,我们采用放射性配基受体结合分析方法检测自然衰老大鼠脑皮层与学习记忆密切相关的线粒体外周苯二氮卓受体(PBRs)结合活性的变化及阿托品对其造成的影响。结果显示：老龄大鼠皮层线粒体PBRs代表受体数量的Bmax值及代表受体结合力的Kd值均显著增高(P<0.05),即受体数量增多但亲和力显著下降。而给予阿托品早期,老龄大鼠PBRs的表达数量明显增加而亲合力显著下降(P<0.05)。最后我们从基因转录水平和蛋白表达水平两个层次重点观察了老龄大鼠脑皮层神经甾体合成的关键蛋白(StAR、P450scc、3β-HSD)表达的变化及其对阿托品的反应性。结果发现,自然衰老大鼠皮层神经甾体合成相关蛋白的mRNA水平和蛋白表达水平均存在不同程度的降低。给予临床剂量阿托品后第4天老龄大鼠皮层P-450scc、3β-HSD的mRNA表达水平显著下降(P<0.05), StAR的mRNA表达水平也有所降低,而第7天这三种蛋白的mRNA表达水平均有所回升。而其蛋白表达水平对阿托品的反应相对滞后,呈现时程性的下降。综上所述,本研究首先观察到自然衰老大鼠基础认知功能下降,这种变化与脑内PBRs受体亲和力降低及甾体合成相关蛋白表达水平下降呈现一定相关性,可能是高龄术后精神障碍的重要机制之一。术前麻醉诱导用药阿托品在临床剂量下对衰老大鼠的学习记忆功能没有明显影响,而对其精神状态会产生一定的影响,但程度比较轻微。抗胆碱药与麻醉药合用对老年患者术后精神障碍的影响有待进一步探讨。更多还原

【Abstract】 The incidence of post-operative mental disorders (POMD) related to anaesthesia increases in elderly patients, which are characterized by post-operative delirium, cognitive impairment, anxiety and depression, and influence post-operative rehabilitation and threaten to life in some cases. The pathophysiology of POMD is poorly understood. Good evidence suggests neurotransmitter disturbances, especially acetylcholine deficiency. In the present study, the effect of anticholinergic agent—atropine which was used in the course of anesthesia induction on psychiatric symptoms and memory were evaluated in aging rats. Our data of morris water maze and Y maze showed the cognition of aging rats was impaired and atropine at clinical dose had no obvious effect on it.. However, atropine had a certain impact on psychiatric symptoms, which was showed in open field and elevated plus maze test. To confirm the precise mechanism of atropine, the quantitive changes of peripheral-type benzodiazepine recepors (PBRs) in brain mitochodria of aging rats and the effect of atropine on it were examined. Our findings showed that compared with 3-month rats, there was an increase in the maximal binding site density (Bmax), with an significant increase in the equilibrium dissociation constant (Kd) in cortex mitochondria of aging rats, which suggested the density of PBRs increased, whereas the binding affinity of PBRs decreased. On 1 st day after atropine treatment, the density of PBRs showed further enhancement but the binding affinity of PBRs further decreased. Meanwhile, we found that compared with 3-month rats, the transcriptional level and the protein level of the three proteins—P450scc、StAR and 3β-HSD which related to the neurosteroids’biosynthesis in the brain decreased. On 4th day after atropine treatment, the transcriptional levels of P450scc and 3β-HSD were significantly lower than those in the control aging rats. However, their levels were restored on 7th day. The changes of the protein level lagged behind the mRNA, and the protein expression decreased in a time-coursing pattern.In conclusion, in this study, the decrease of the basal level of aged rats cognition, the binding activity of PBRs in brain mitochodria of aging rats and the expression of the proteins regard to neurosteroids de novo synthesis were observed, which maybe related to the susceptibility of old age to POMD. Anesthesia induction agents-atropine had no significant effect on memory function, but exerted some effect on psychiatric symptoms, implicating the influence of the combination of anticholinergic agents and anesthetics on POMD in old patients need to be further investigated.更多还原