本文選題：術(shù)后認(rèn)知功能障礙 + NMDA受體��； 參考：《中國(guó)人民解放軍醫(yī)學(xué)院》2016年博士論文

【摘要】：第一部分 手術(shù)創(chuàng)傷對(duì)老年小鼠POCD行為學(xué)影響目的：通過左肝外葉切除術(shù)構(gòu)建C57BL/6老年小鼠術(shù)后認(rèn)知功能障礙(postoperative cognitive dysfunction or decline,POCD)模型,探索老年小鼠POCD模型的構(gòu)建,以及手術(shù)創(chuàng)傷對(duì)老年小鼠術(shù)后認(rèn)知功能的影響。方法：15月齡健康C57BL/6老年小鼠共80只,按隨機(jī)數(shù)組表法分為空白對(duì)照組、麻醉組、假手術(shù)組和手術(shù)組。小鼠在術(shù)前5天接受訓(xùn)練,每天3次,尋找固定隱藏平臺(tái)。第6天接受左肝外葉切除術(shù)。術(shù)后第1,3,7天用“空間探索實(shí)驗(yàn)”評(píng)價(jià)其空間記憶能力,記錄穿臺(tái)次數(shù)和目標(biāo)象限停留時(shí)間百分比。結(jié)果：在空間獲得性實(shí)驗(yàn)中,各組C57BL/6老年小鼠學(xué)習(xí)記憶能力隨著時(shí)間的延長(zhǎng)顯著提高(P0.05)并在第5天趨于穩(wěn)定,且組間沒有差異。Morris水迷宮測(cè)試?yán)夏晷∈蟠┡_(tái)次數(shù)和目標(biāo)象限停留百分比結(jié)果顯示：與空白對(duì)照組比較,麻醉組無差異,假手術(shù)組(除術(shù)后7d)和手術(shù)組明顯下降(P0.05)：與假手術(shù)組相比,手術(shù)組在各時(shí)間點(diǎn)明顯下降(P0.05)。組內(nèi)比較,與術(shù)后1d比較,空白組和麻醉組術(shù)后3d、7d無差異;假手術(shù)組術(shù)后3d、7d逐漸恢復(fù),至術(shù)后7d時(shí)間點(diǎn)基本恢復(fù)正常(P0.05);手術(shù)組術(shù)后3d、7d雖有所恢復(fù),但仍較正常值明顯下降(P0.05)。結(jié)論：左肝外葉切除術(shù)能成功建立C57BL/6老年小鼠POCD模型,且空間記憶能力的損傷在肝切除術(shù)老年小鼠中較假手術(shù)老年小鼠重。第二部分POCD與NMDA受體-NF-Kappa B-nNOS信號(hào)通路的關(guān)系實(shí)驗(yàn)一目的：對(duì)C57BL/6老年小鼠進(jìn)行手術(shù)并抑制圍術(shù)期應(yīng)激因素(鎮(zhèn)痛,鎮(zhèn)靜),研究中樞神經(jīng)POCD過程中NMDA受體-NFKB-nNOS信號(hào)通路的激活。方法：15月齡健康C57BL/6老年小鼠共80只,按隨機(jī)數(shù)字表法分為空白對(duì)照組、麻醉組、假手術(shù)組和手術(shù)組。觀察內(nèi)容如下：分別于術(shù)后1,3,7d三個(gè)時(shí)間點(diǎn),各組分別有8只動(dòng)物斷頭取腦,ELISA測(cè)定左側(cè)腦組織NMDA受體NR2B,nNOS,NF-κB,NOS以及NO含量測(cè)定;右側(cè)腦組織RT-PCR測(cè)定突觸素mNRA, PSD-95蛋白mNRA.結(jié)果：檢測(cè)結(jié)果顯示,與空白對(duì)照組比較,各檢測(cè)指標(biāo)(NMDA受體NR2B，NF-κB, nNOS, NOS)蛋白水平以及NO含量,麻醉組在術(shù)后各時(shí)間點(diǎn)無差異;假手術(shù)組(除外術(shù)后7d時(shí)間點(diǎn))和手術(shù)組在術(shù)后各時(shí)間點(diǎn)明顯下降(P0.05)：與假手術(shù)組比較,各時(shí)間點(diǎn)手術(shù)組明顯下降(P0.05)。組內(nèi)比較：與術(shù)后1d比較,假手術(shù)組至7d時(shí)基本恢復(fù)正常(P0.05);手術(shù)組則逐漸下降,至7d時(shí)降至最低(P0.05)。RT-PCR測(cè)定老年小鼠腦內(nèi)突觸素mRNA和PSD-95mRNA表達(dá)水平發(fā)現(xiàn),與空白對(duì)照組比較,麻醉組在術(shù)后各時(shí)間點(diǎn)無差異;假手術(shù)組(除外術(shù)后7d時(shí)間點(diǎn))和手術(shù)組在術(shù)后各時(shí)間點(diǎn)明顯下降(P0.05);與假手術(shù)組比較，各時(shí)間點(diǎn)手術(shù)組明顯下降(P0.05)。組內(nèi)比較：與術(shù)后1d比較,假手術(shù)組老年小鼠至7d時(shí)基本恢復(fù)正常(P0.05);手術(shù)組則逐漸下降,至7d時(shí)降至最低(P0.05)。結(jié)論：C57BL/6老年小鼠在構(gòu)建POCD模型后,腦內(nèi)NMDA受體、NF-κB、 nNOS蛋白水平的變化趨勢(shì)均呈漸進(jìn)性下降,且7d為最低值。這與腦內(nèi)與突觸相關(guān)的突觸素mRNA和PSD-95蛋白mRNA表達(dá)趨勢(shì)相同,因此提示腦內(nèi)NMDA受體、NF-κB、nNOS蛋白水平的變化是引起老年小鼠POCD的可能機(jī)制。實(shí)驗(yàn)二目的：對(duì)C57BL/6老年小鼠進(jìn)行手術(shù),抑制圍術(shù)期應(yīng)激因素(鎮(zhèn)痛,鎮(zhèn)靜),通過應(yīng)用NMDA受體激動(dòng)劑(15mg/kg NMDA)驗(yàn)證老年小鼠POCD過程中存在NMDA受體-NFκB-nNOS通路的激活。方法：15月齡健康C57BL/6老年小鼠共56只，按隨機(jī)數(shù)字表法分為空白對(duì)照組、假手術(shù)組和手術(shù)組。腹腔內(nèi)注射NMDA受體激動(dòng)劑(15mg/kgNMDA) 1小時(shí)后行手術(shù)。觀察內(nèi)容如下：分別于術(shù)后1,3,7d三個(gè)時(shí)間點(diǎn),各組分別有8只動(dòng)物斷頭取腦,ELISA測(cè)定左側(cè)腦組織NMDA受體NR2B,nNOS,NF-KB,NOS以及NO含量測(cè)定;右側(cè)腦組織RT-PCR測(cè)定突觸素mRNA,PSD-95蛋白mRNA.結(jié)果：檢測(cè)結(jié)果顯示,與空白對(duì)照組比較,各檢測(cè)指標(biāo)(NMDA受體NR2B、 NF-κB、nNOS、NOS)蛋白水平以及NO含量，，假手術(shù)組在術(shù)后各時(shí)間點(diǎn)無差異：手術(shù)組在術(shù)后各時(shí)間點(diǎn)明顯下降(P0.05)。手術(shù)組內(nèi)：與術(shù)后1d比較,其余時(shí)間點(diǎn)明顯下降(P0.05),但術(shù)后7d與3d比較則無差異(P0.05)。RT-PCR測(cè)定老年小鼠腦內(nèi)突觸素mRNA和PSD-95mRNA表達(dá)水平發(fā)現(xiàn)，與空白對(duì)照組比較，假手術(shù)組在術(shù)后各時(shí)間點(diǎn)(除術(shù)后1d)無差異;手術(shù)組在術(shù)后各時(shí)間點(diǎn)明顯下降(P0.05)。手術(shù)組內(nèi)：與術(shù)后1d比較,其余時(shí)間點(diǎn)明顯下降(P0.05),但術(shù)后7d與3d比較則無差異(P0.05)。結(jié)論：腹腔內(nèi)注射NMDA受體激動(dòng)劑后，發(fā)現(xiàn)老年P(guān)OCD小鼠腦內(nèi)海馬組織NMDA受體NR2B、NF-κB、nNOS蛋白水平以及NO含量的降低趨勢(shì)減緩,且7d與3d比較無明顯差異，這與神經(jīng)元突觸素mRNA以及PSD-95mRNA表達(dá)趨勢(shì)相同。提示腦內(nèi)NMDA受體,NF-κB,nNOS蛋白水平的變化是引起老年小鼠POCD的可能機(jī)制，并為我們治療POCD提供了新的思路。
[Abstract]:Part one the effect of surgical trauma on the behavior of POCD in aged mice objective by left hepatic lobectomy to construct C57BL/6 aged mice of postoperative cognitive dysfunction (postoperative cognitive dysfunction or decline, POCD) model was constructed to explore the old mice POCD model, as well as the influence of surgical trauma on postoperative cognitive function in elderly mice. Methods: 15 month old a total of 80 healthy aged C57BL/6 mice, according to the random array table were divided into blank control group, anesthesia group, sham operation group and operation group. The mice in the 5 days before training, 3 times a day, looking for hidden fixed platform. Sixth days underwent left hepatic lobectomy. 1,3,7 days after operation with "space to explore the spatial memory ability evaluation experiment, record the times across the platform and the percentage of target quadrant time. Results: experiments in space, each C57BL/6 in aged mice learning and memory ability with The time significantly improve (P0.05) and tend to be stable in fifth days, and there were no group differences in the.Morris water maze test in aged mice Taiwan number and target quadrant percentage results show: compared with the control group, no difference in anesthesia group, sham operation group (except 7D) and the operation group decreased significantly (P0.05): compared with sham operation group, operation group was significantly decreased at each time point (P0.05). Compared with the comparison group, postoperative 1D, blank group and anesthesia group after 3D, 7d no difference; sham operation group after 3D, 7d gradually recovered to the recovery time of postoperative normal base 7d (P0.05); surgery group 3D 7d, despite the recovery, but still lower than the normal value decreased significantly (P0.05). Conclusion: left hepatic lobectomy can be successfully established C57BL/6 POCD in the senile mice model, and the spatial memory ability of injury during liver resection in aged mice compared with sham operated mice. Second elderly part POCD The relationship between NMDA and -NF-Kappa receptor B-nNOS signaling pathway Objective: a surgical C57BL/6 in old mice and inhibit the perioperative stress factors (analgesia, sedation), activation of central nerves in the process of POCD NMDA receptor -NFKB-nNOS signaling pathway. Methods: 15 month old healthy C57BL/6 mice aged 80, anesthesia group randomly divided into blank control group, sham operation group and operation group. Observe the contents are as follows: respectively after 1,3,7d three time points, each group has 8 animal brains were removed for determination of NMDA, ELISA receptor NR2B, left brain tissue nNOS, NF- kappa B, NOS and NO determination of content; the right side of the brain tissue was determined by RT-PCR the expression of mNRA, PSD-95 protein mNRA. results: test results show that, compared with the control group, all indexes (NMDA receptor NR2B, NF- kappa B, nNOS, NOS) protein level and the content of NO, anesthesia group at each time point after surgery no difference Different; sham operation group (except after 7d time point) and the operation group at each time point after operation was significantly decreased (P0.05) compared with the sham operation group, operation group at each time point was significantly decreased (P0.05). Group comparison: compared with postoperative 1D, sham operation group and 7d returned to normal (P0.05); operation group decreased to the lowest at 7d (P0.05).RT-PCR expression level was found the expression of mRNA and PSD-95mRNA in elderly mice, compared with the blank control group, anesthesia group at each time point after operation there is no difference; sham operation group (except after 7d time point) and the operation group in at each time point after operation was significantly decreased (P0.05); compared with the sham operation group, operation group at each time point was significantly decreased (P0.05). Group comparison: compared with postoperative 1D, sham operation group aged mice to 7d normal (P0.05); operation group decreased to the lowest at 7d (P0.05). Conclusion: the old C57BL/6 In mice in the POCD model, NMDA receptors in the brain, NF- kappa B, the change trend of nNOS protein level showed a gradual decline, and 7d is the lowest. The brain and synaptic associated synaptophysin mRNA and PSD-95 protein expression of mRNA in the same trend, thus suggesting that NMDA receptors in the brain, the expression of NF- B. Changes in the level of nNOS protein is the possible mechanism of aged mice caused by POCD. Experiment two objective: surgical C57BL/6 in old mice, inhibition of perioperative stress factors (analgesia, sedation), through the application of NMDA receptor agonist (15mg/kg NMDA) of NMDA receptor activation -NF B-nNOS pathway of the validation process of aged mice. Methods POCD 15 month old: C57BL/6 total of 56 healthy aged mice, were randomly divided into control group, sham operation group and operation group. Intraperitoneal injection of NMDA receptor agonist (15mg/kgNMDA) 1 hours after surgery. Observe the contents are as follows: after operation. 1,3,7d three time points, each group has 8 animal brains were removed for determination of NMDA, ELISA receptor NR2B, left brain tissue nNOS, NF-KB, NOS and NO determination of content; the right side of the brain tissue RT-PCR determination of synapsin mRNA, PSD-95 protein mRNA. results: test results show that, compared with the control group, all indexes (NMDA receptor NR2B, NF-, nNOS, NOS) kappa B protein level and the content of NO, the sham operation group at each time point after operation, no difference in operation group at each time point after operation was significantly decreased (P0.05). The operation group: compared with 1D after operation, the rest of the time points were significantly decreased (P0.05), but after the operation 7d and 3D were no difference (P0.05) determination of.RT-PCR expression levels of synaptophysin mRNA and PSD-95mRNA found in the brain of aged mice, compared with the blank control group, sham operation group at each time point after operation (except 1D) no difference; surgical group at each time point after operation was significantly decreased (P0.05) operation group. In: Compared with the 1D after the operation, the rest of the time points were significantly decreased (P0.05), but the postoperative 7d compared with 3D had no difference (P0.05). Conclusion: intraperitoneal injection of NMDA receptor agonist, was found in the hippocampus of aged POCD mice NMDA receptor NR2B, NF- kappa B, slow decrease the protein level of nNOS and NO the content of 7D and 3D had no significant difference, this is the same as the neurons of synapsin mRNA and the expression of PSD-95mRNA receptors in the brain. The trend suggests that NMDA, NF- kappa B, nNOS protein level changes is the possible mechanism of aged mice caused by POCD, and provides a new way for us to treat POCD.

【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R619

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