本文選題：艾司西酞普蘭 + 帕金森病　； 參考：《河北醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:帕金森病(Parkinson's disease,PD)是常發(fā)于中老年人的中樞神經(jīng)系統(tǒng)變性疾病,主要臨床表現(xiàn)為震顫、強(qiáng)直、運(yùn)動弛緩、姿勢平衡障礙等運(yùn)動癥狀,此外,常伴發(fā)抑郁、焦慮、便秘、睡眠障礙、認(rèn)知功能減退等非運(yùn)動癥狀。艾司西酞普蘭(escitalopram,ESC)是新型的高選擇性5-羥色胺再攝取抑制劑(Selective Serotonin Reuptake Inhibitor,SSRI),對受體的選擇性較高,對肝藥酶P450的抑制作用小,不良反應(yīng)及藥物相關(guān)反應(yīng)也較少,安全性較高,在臨床廣泛應(yīng)用于廣泛性焦慮、抑郁癥。本文旨在探討ESC對PD小鼠模型運(yùn)動、認(rèn)知功能的影響。方法:將37只11周齡23~30g C57BL/6J健康雄性小鼠隨機(jī)分為3組:1正常對照組(CON組):正常健康小鼠,腹腔注射0.1ml生理鹽水;2急性PD組(PD組):采用急性腹腔注射MPTP制作急性PD模型小鼠,20mg/kg MPTP腹腔注射,每2h注射1次,共4次;3 ESC預(yù)處理組:在制備PD模型前3天,每日對小鼠進(jìn)行10mg/kg ESC腹腔注射,每天1次,共3天;以MPTP制備PD模型為第0天,第-3至-1天進(jìn)行爬桿實驗適應(yīng)性訓(xùn)練及ESC預(yù)處理,第2-7天進(jìn)行Morris水迷宮實驗,第8天進(jìn)行爬桿實驗,第9天按照預(yù)定條件取各組小鼠大腦,采用Western blot觀察小鼠大腦海馬BDNF的變化,采用免疫組織化學(xué)觀察小鼠海馬細(xì)胞個數(shù)變化,以及觀察黑質(zhì)-紋狀體酪氨酸羥化酶陽性(tyrosine hydroxylase positive,TH+)細(xì)胞的改變。結(jié)果:1黑質(zhì)及紋狀體TH+細(xì)胞的改變第15d小鼠黑質(zhì)行TH免疫組織化學(xué)染色,結(jié)果顯示:PD組小鼠黑質(zhì)的殘留TH+細(xì)胞皺縮,不飽滿,有梭形改變,突起減少。PD組與CON組相比,黑質(zhì)TH+細(xì)胞數(shù)較正常下降49.31%,ESC預(yù)處理組與CON組相比,黑質(zhì)TH+細(xì)胞數(shù)較正常下降32.35%。差異均有統(tǒng)計學(xué)意義(P0.05)。PD組與CON組相比,PD組紋狀體TH+細(xì)胞的平均光密度(mean optical density,MOD)較CON組下降了69.55%,ESC預(yù)處理組較CON組下降了51.46%,差異有統(tǒng)計學(xué)意義(P0.05)。2 ESC對PD模型小鼠認(rèn)知功能影響2.1 ESC對PD模型小鼠學(xué)習(xí)功能的影響PD模型造模成功后,在第2天進(jìn)行Morris水迷宮實驗測試各組小鼠的學(xué)習(xí)功能。通過對定向航行實驗數(shù)據(jù)進(jìn)行重復(fù)測量檢驗,各組小鼠的潛伏期均逐漸縮短(CON組=ESC組PD組),CON組與PD組差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組差異無統(tǒng)計學(xué)意義(P0.05),PD組與ESC組差異有統(tǒng)計學(xué)意義(P0.05),CON組和ESC組較PD組潛伏期明顯縮短。2.2 ESC對PD模型小鼠記憶功能的影響通過第6天水迷宮檢測,CON組小鼠與PD組小鼠穿過平臺次數(shù)及穿越平臺路程比率差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組差異無統(tǒng)計學(xué)意義(P0.05),ESC預(yù)處理組有穿越平臺次數(shù)增加及穿越平臺路程比率升高但與PD組差異無統(tǒng)計學(xué)意義(P0.05)。小鼠的記憶狀況為CON組≥ESC組≥PD組,且CON組PD組,說明PD小鼠的記憶能力明顯下降,ESC預(yù)處理組的記憶能力在一定程度上有所改善,但是尚不能與PD組有明顯區(qū)別。3 ESC對PD模型小鼠海馬區(qū)BDNF含量的影響通過Western blot檢測各組小鼠海馬區(qū)BDNF含量,結(jié)果顯示PD組(0.09±0.01)BDNF含量明顯低于CON組(0.64±0.27)及ESC預(yù)處理組(0.57±0.05),差異有統(tǒng)計學(xué)意義(P0.05),而CON組與ESC預(yù)處理組無差異(P0.05)。4 ESC對PD模型小鼠海馬區(qū)細(xì)胞個數(shù)的影響小鼠海馬區(qū)細(xì)胞經(jīng)免疫組化膽堿能染色后,結(jié)果顯示CON組細(xì)胞數(shù)(100.9±10.8)個與PD組小鼠(84±7.0)個差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組(94.8±7.6)個差異無統(tǒng)計學(xué)意義(P0.05),PD組與ESC預(yù)處理組差異有統(tǒng)計學(xué)意義(P0.05),CON組和ESC組平均海馬細(xì)胞個數(shù)明顯高于PD組。5 ESC對PD模型小鼠運(yùn)動功能的影響在第7d進(jìn)行的Morris水迷宮試驗檢測各組小鼠游泳速度,結(jié)果顯示:PD組與CON組、ESC預(yù)處理組相比游泳速度顯著降低,差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組間的游泳速度相比,差異無統(tǒng)計學(xué)意義(P0.05)。在MPTP造模第8d進(jìn)行爬桿實驗,檢測各組小鼠的運(yùn)動功能。結(jié)果顯示:CON組與PD組差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組差異無統(tǒng)計學(xué)意義(P0.05),PD組與ESC組有差異有統(tǒng)計學(xué)意義(P0.05),CON組與ESC預(yù)處理組小鼠的爬桿時間明顯低于PD組。結(jié)論:1急性腹腔注射MPTP可以成功制作PD模型,在PD模型制作初期運(yùn)動能力損傷嚴(yán)重,PD小鼠的震顫、強(qiáng)直癥狀明顯,24h后,癥狀逐漸減輕至消失。MPTP對C57BL/6J小鼠的黑質(zhì)-紋狀體多巴胺能神經(jīng)元和神經(jīng)纖維造成了嚴(yán)重?fù)p害。2 MPTP對C57BL/6J小鼠的學(xué)習(xí)及記憶能力有損害,認(rèn)知功能明顯下降。ESC可以改善急性PD小鼠的學(xué)習(xí)能力,但對MPTP造成的記憶損害無明顯改善;ESC預(yù)處理可以緩解急性PD小鼠的運(yùn)動功能障礙。3 ESC預(yù)處理對PD小鼠的保護(hù)作用可能與ESC能夠保護(hù)海馬和黑質(zhì)多巴胺神經(jīng)元以及提高海馬區(qū)BDNF有關(guān)。
[Abstract]:Objective: Parkinson's disease (Parkinson's disease, PD) is a central nervous system degenerative disease often occurring in middle-aged and old people. The main clinical manifestations are tremor, ankylosis, movement relaxation, postural balance disorder and other sports symptoms. In addition, it often accompanied by depression, anxiety, constipation, sleep barrier, cognitive impairment and other non motor symptoms. (escitalopr (escitalopr) Am, ESC) is a new high selective 5- serotonin reuptake inhibitor (Selective Serotonin Reuptake Inhibitor, SSRI), which has higher selectivity to the receptor, less inhibition to the liver enzyme P450, less adverse reactions and drug related reactions and high safety. It is widely used in widespread anxiety and depression in the bed. This paper aims to explore ESC. The influence of cognitive function on PD mouse model movement. Methods: 37 11 weeks old 23~30g C57BL/6J healthy male mice were randomly divided into 3 groups: 1 normal control group (group CON): normal healthy mice, intraperitoneal injection of 0.1ml physiological saline; 2 acute PD group (group PD): acute peritoneal injection of MPTP to make acute PD model mice, 20mg/kg MPTP intraperitoneal injection, each 2H 1 times, a total of 4 times; 3 ESC pretreatment group: 3 days before the preparation of the PD model, the mice were intraperitoneally injected with 10mg/kg ESC daily, 1 times a day, for a total of 3 days; MPTP was used to prepare PD model for zeroth days, -3 to -1 days for climbing pole experiment adaption training and ESC preprocessing, the 2-7 day Morris water maze experiment, eighth days climbing pole experiment, Ninth days according to preconditioning. The changes of BDNF in the hippocampus of mice were observed by Western blot. The changes in the number of hippocampal cells in mice were observed by immunohistochemistry and the changes of tyrosine hydroxylase positive (TH+) cells were observed in the substantia nigra and striatum (tyrosine hydroxylase positive, TH+). Results: the changes of 1 substantia nigra and striatum TH+ cells were changed by first 5D murine substantia nigra was stained with TH immunohistochemical staining. The results showed that the residual TH+ cells in the substantia nigra of the PD group were crinkled, not full, and there was a change of spindle shape. The number of TH+ cells in the substantia nigra decreased by 49.31% compared with the CON group in the.PD group, and the number of TH+ cells in the ESC preconditioning group compared with the CON group was statistically significant (P) was significantly lower than that of the normal 32.35%. (P). 0.05) compared with the CON group, the average light density (mean optical density, MOD) of the PD group was 69.55% lower than the CON group in the group PD, and the ESC pretreatment group was 51.46% lower than the CON group. The difference was statistically significant (P0.05) influenced the cognitive function of the model mice 2.1. The Morris water maze test was used to test the learning function of the mice in the Morris water maze test. Through the repeated measurement of the directional navigation test data, the incubation period of the mice was gradually shortened (group PD of group CON =ESC). The difference between the CON group and the PD group was statistically significant (P0.05), and there was no significant difference between the CON group and the ESC pretreatment group (P0.05), PD group. The difference between group ESC and group ESC was statistically significant (P0.05). The incubation period of group CON and ESC significantly shortened the effect of.2.2 ESC on the memory function of PD model mice through sixth days water maze, and there were statistical significance (P0.05) in the number of the CON group and the PD group through the platform times and the crossing platform, and there was no difference between the CON group and the pretreatment group. The study significance (P0.05), ESC pretreated group increased the number of crossing platform and the increase of cross platform road ratio, but there was no significant difference with the PD group (P0.05). The memory status of the mice was CON group > ESC group > PD group, and CON group PD group, indicating that the memory ability of PD mice descended obviously, and the memory ability of ESC pretreatment group was certain to some extent. However, the effect of.3 ESC on the BDNF content in hippocampus of PD model mice was not significantly different from that of PD group. The content of BDNF in the hippocampus of each group was detected by Western blot. The results showed that the content of PD group (0.09 + 0.01) BDNF was significantly lower than that of CON group (0.64 + 0.27) and ESC preconditioning group (0.57 + 0.05), and the difference was statistically significant. The effect of pre treated group (P0.05).4 ESC on the number of cells in the hippocampus of PD model mice was affected by immunohistochemical cholinergic staining, the results showed that the number of cells in the CON group (100.9 + 10.8) was significantly different from that of the PD group (84 + 7) (P0.05), and there was no significant difference between the CON group and the ESC preconditioning group (94.8 + 7.6). (P0.05), the difference between group PD and ESC preconditioning group was statistically significant (P0.05). The average number of hippocampal cells in group CON and ESC was significantly higher than that of PD group.5 ESC on the movement function of PD model mice. The swimming speed of mice in 7d Morris water maze test was detected in 7d Morris water maze test. The difference was statistically significant (P0.05). There was no significant difference in swimming speed between group CON and ESC preconditioning group (P0.05). The exercise function of mice in each group was detected in MPTP model 8D. The results showed that there was significant difference between group CON and PD group (P0.05), and there was no significant difference between the CON group and the ESC pretreatment group (P0.05). P0.05), there was a significant difference between group PD and group ESC (P0.05). The time of climbing pole of mice in group CON and ESC preconditioning group was obviously lower than that of group PD. Conclusion: 1 acute peritoneal injection of MPTP can make PD model successfully. In the early stage of making PD model, the exercise ability is seriously damaged, PD mice tremble, and the symptoms of ankylosis are obvious. After 24h, the symptoms gradually lighten to disappear. P had serious damage to the nigrostriatal dopaminergic neurons and nerve fibers in C57BL/6J mice..2 MPTP was impaired in the learning and memory ability of C57BL/6J mice. The cognitive decline of.ESC could improve the learning ability of acute PD mice, but the memory damage caused by MPTP was not significantly improved; ESC preconditioning could alleviate the acute toxicity of C57BL/6J. The protective effect of.3 ESC preconditioning in PD mice on PD mice may be related to the protective effect of ESC on the protection of hippocampus and substantia nigra dopamine neurons and the enhancement of BDNF in the hippocampus.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R742.5;R-332

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本文編號：1907208