金剛烷胺減緩抑郁模型大鼠認知功能的損傷及其機理研究
發(fā)布時間：2019-01-10 12:51
【摘要】：抑郁癥(depression)是一種由多種原因引起的心境障礙或情感障礙,以顯著而持久的心境低落為主要臨床特征,患者常常伴有明顯的認知功能障礙,包括執(zhí)行功能障礙、記憶障礙、注意障礙等。抑郁癥的發(fā)病機制復雜,如有研究報道在生活中遭遇過度的挫折和刺激會引發(fā)抑郁。據(jù)此,在基礎臨床研究中,常常將各種不同的應激刺激施加于動物身上來模擬抑郁的發(fā)展并研究其發(fā)病機制及治療。其中,慢性不可預知性應激模型(chronic unpredictable stress, CUS)是目前應用較廣泛且獲得學術界普遍認可的抑郁癥動物模型之一。它主要模擬了抑郁的核心表現(xiàn),即快感缺乏。研究發(fā)現(xiàn)慢性不可預知性應激模型大鼠的空間學習及靈活性顯著下降。在慢性應激的刺激下,海馬CA3區(qū)神經(jīng)元萎縮、樹突棘形態(tài)嚴重受損、齒狀回區(qū)神經(jīng)元的再生減少,且其突觸可塑性也受到了嚴重的損傷,這些改變與其導致的認知功能損傷密切相關。金剛烷胺(amantadine, AMA)是一種三環(huán)癸烷氨基衍生物。最早它主要用于流行性感冒的治療和預防,后來發(fā)現(xiàn)其具有治療帕金森氏綜合癥的作用。其可能的機制是由于它能促進紋狀體內多巴胺能神經(jīng)末梢釋放多巴胺(dopamine,DA)。此外,它還能通過綁定N-甲基-D-天冬氨酸受體(N-methyl-D-aspartic acid, NMDA)和阻斷谷氨酸進入細胞起到對神經(jīng)元的保護作用。與美金剛(memantine,MEM)一樣,它是一種低中度親和力、非競爭性的NMDA受體拮抗劑。實驗室的前期研究發(fā)現(xiàn),美金剛能改善抑郁模型大鼠的抑郁樣癥狀,并對抑郁模型大鼠水迷宮反向學習的損傷具有恢復傾向,并指出其可能是通過調節(jié)NR2B受體,部分恢復了應激大鼠受損的突觸可塑性。金剛烷胺作為臨床應用的藥品,與美金剛結構相似,但是其價格低廉、副作用明確,耐受性好,使用歷史也較長。因此在本研究中,將主要探討金剛烷胺是否具有減緩抑郁模型大鼠的認知功能損傷,及其可能的細胞學和分子生物學機制。本實驗選用雄性Wistar大鼠,隨機分成四組：對照組(CON)、AMA對照給藥組(CON+AMA)、應激模型組(STRESS)、AMA模型給藥組(STRESS+AMA)。應激模型組采用CUS模型,并結合孤獨飼養(yǎng),以此來模擬抑郁樣的行為表現(xiàn),用糖水偏好實驗及體重變化來驗證建模是否成功。水迷宮實驗主要檢測動物空間記憶功能及再認知的靈活性。應用電生理技術記錄海馬Schaffer側枝到CA1的長時程增強(long term potentiation, LTP)和去增益(depotentiation, DP)。應用Western blot技術檢測海馬中NMDA受體的功能亞單位NR2B及突觸后致密蛋白95 (postsynapticdensity-95, PSD-95)的相對表達量,以此來了解金剛烷胺對抑郁樣模型大鼠空間認知功能受損的可能療效,并探討其潛在的機制。主要實驗結果如下：(1) STRESS組大鼠體重增長及糖水消耗百分比顯著低于正常對照組,而金剛烷胺明顯增加了應激模型組大鼠體重增長緩慢的趨勢,并提高了其糖水消耗百分比。(2)在定位航行階段,與正常對照組相比,STRESS組大鼠的逃避潛伏期明顯延長,而金剛烷胺顯著縮短了STRESS組大鼠的逃避潛伏期。并在空間探測階段,應激模型組大鼠的目標象限停留時間百分比和平臺穿越次數(shù)顯著減少,而AMA給藥后明顯增加。(3)在空間反向訓練階段,STRESS組大鼠需要更多的時間找到平臺所在的新位置,而給予金剛烷胺則顯著地減少了應激大鼠的逃避潛伏期。此外,新目標象限停留時間百分比和平臺穿越次數(shù)在STRESS組大鼠中較CON組大鼠明顯減少,AMA顯著增加了平臺穿越次數(shù),新目標象限目標百分比有所增加但無統(tǒng)計學差異。(4)與對照組相比,STRESS組大鼠海馬CA1區(qū)的LTP顯著降低而去增益明顯增加,給予金剛烷胺之后LTP顯著增加且去增益明顯降低。(5) Western blot實驗結果顯示STRESS組大鼠海馬中NR2B及PSD-95的相對表達量明顯低于CON組和STRESS+AMA組。根據(jù)以上的結果,我們得到如下結論：(1)金剛烷胺能有效的減緩應激模型大鼠快感缺乏、體重減輕等癥狀,表現(xiàn)出潛在的抗抑郁效果。(2)金剛烷胺能降低抑郁模型大鼠的認知功能損傷程度,其潛在的機制可能是增加了海馬中NR2B和PSD-95的相對表達量,從而阻止了CA3-CA1的LTP和去增益的雙向可塑性失衡,進而減緩了抑郁模型大鼠的空間認知損傷。
[Abstract]:Depression is a kind of mood disorder or affective disorder, which is caused by a variety of reasons, which is characterized by a significant and persistent state of mind and is often accompanied by obvious cognitive impairment, including executive dysfunction, memory disorder, attention disorder, and the like. The pathogenesis of depression is complex, as it is reported that excessive setbacks and irritation in life can trigger depression. Therefore, in the basic clinical study, various stress stimulation is often applied to the animal to simulate the development of the depression and to study the pathogenesis and treatment of the depression. The chronic unpredictable stress model (CUS) is one of the most widely accepted models of depression in the academic community. It mainly simulates the core performance of depression, that is, the lack of pleasure. The study found that there was a significant decrease in the spatial learning and the flexibility of the rats with chronic unpredictable stress model. Under the stimulation of chronic stress, the neurons of the CA3 region of the hippocampus atrophy, the shape of the dendritic spine is severely damaged, the regeneration of the dentate gyrus neurons is reduced, and the synaptic plasticity of the dentate gyrus is also severely damaged, and the changes are closely related to the cognitive function damage caused by the changes. amantadine (AMA) is a tricyclic decane amino derivative. It was the first to be used for the treatment and prevention of influenza, and it was later found to have the effect of treating Parkinson's disease. The possible mechanism is that it promotes dopamine in the striatum to release dopamine (DA). In addition, it can play a protective role on neurons by binding the N-methyl-D-aspartate receptor (N-methyl-D-aspartic acid, NMDA) and blocking glutamate. Like memantine (MEM), it is a low medium affinity, non-competitive NMDA receptor antagonist. The early study of the laboratory found that memantine can improve the depression-like symptoms in the depressed model rats and have a tendency to recover the damage to the water maze of the depressed model rats, and point out that it may be through the regulation of the NR2B receptor, and the partial recovery of the stress-induced synaptic plasticity in the stress rats. As a medicine for clinical application, the amantadine is similar to that of the memantine structure, but has the advantages of low price, clear side effect, good tolerance and long use history. Therefore, in this study, it will be mainly discussed whether the amantadine has the cognitive function damage of the depression model rats, and the possible mechanism of cytology and molecular biology. Male Wistar rats were randomly divided into four groups: control group (CON), AMA control group (CON + AMA), stress model group (STRESS) and AMA model group (STRESS + AMA). In the stress model group, the CUS model was used to simulate the behavior of the depression, and the experiment and weight change of the sugar water were used to verify the success of the model. The experiment of water maze mainly detects the memory function of the animal and the flexibility of the re-cognition. The long term potentiation (LTP) and de-gain (DP) of the hippocampal Schaffer side branch to CA1 were recorded by electrophysiology. The relative expression of the functional subunit NR2B and postsynaptic compact protein 95 (PSD-95) of the NMDA receptor in the hippocampus was detected by Western blot. The results of the main experiments were as follows: (1) The weight gain and the percentage of sugar water consumption in the STRESS group were significantly lower than that of the control group, and the amantadine significantly increased the weight gain of the rats in the stress model group and increased the percentage of sugar water consumption. (2) Compared with the normal control group, the escape latency of the STRESS group was significantly prolonged compared with the normal control group, and the amantadine significantly shortened the escape latency of the STRESS group rats. At the stage of spatial detection, the percentage of the target quadrant retention time and the number of platform-crossing times in the stress model group were significantly reduced, and the AMA was significantly increased after administration. (3) In the stage of space reverse training, the STRESS rats need more time to find the new position of the platform, and the amantadine significantly reduces the escape latency of the stress rats. in addition, that percentage of residence time of the new target quadrant and the number of platform traverse decreased significantly in the CON group in the STRESS group, and AMA significantly increased the number of platform crossing, and the target percentage of the new target quadrant increased without statistical difference. (4) Compared with the control group, the LTP in the CA1 region of the rats in the STRESS group was significantly reduced and the gain was significantly increased, and the LTP was significantly increased after the amantadine was given and the degain was significantly reduced. (5) The results of Western blot showed that the relative expression of NR2B and PSD-95 in the hippocampus of the rats was significantly lower than that of the CON group and the STRESS + AMA group. Based on the above results, we have the following conclusion: (1) The amantadine can effectively slow down the symptoms of the stress model, such as the lack of the pleasure, the weight loss, and the like, and show the potential antidepressant effect. (2) The potential mechanism of amantadine to decrease the degree of cognitive function injury in the depressed model rats may be to increase the relative expression of NR2B and PSD-95 in the hippocampus, thus preventing the two-way plastic imbalance of the LTP and de-gain of CA3-CA1, so that the spatial cognitive impairment of the depression model rats is reduced.
【學位授予單位】：南開大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R749.4
[Abstract]:Depression is a kind of mood disorder or affective disorder, which is caused by a variety of reasons, which is characterized by a significant and persistent state of mind and is often accompanied by obvious cognitive impairment, including executive dysfunction, memory disorder, attention disorder, and the like. The pathogenesis of depression is complex, as it is reported that excessive setbacks and irritation in life can trigger depression. Therefore, in the basic clinical study, various stress stimulation is often applied to the animal to simulate the development of the depression and to study the pathogenesis and treatment of the depression. The chronic unpredictable stress model (CUS) is one of the most widely accepted models of depression in the academic community. It mainly simulates the core performance of depression, that is, the lack of pleasure. The study found that there was a significant decrease in the spatial learning and the flexibility of the rats with chronic unpredictable stress model. Under the stimulation of chronic stress, the neurons of the CA3 region of the hippocampus atrophy, the shape of the dendritic spine is severely damaged, the regeneration of the dentate gyrus neurons is reduced, and the synaptic plasticity of the dentate gyrus is also severely damaged, and the changes are closely related to the cognitive function damage caused by the changes. amantadine (AMA) is a tricyclic decane amino derivative. It was the first to be used for the treatment and prevention of influenza, and it was later found to have the effect of treating Parkinson's disease. The possible mechanism is that it promotes dopamine in the striatum to release dopamine (DA). In addition, it can play a protective role on neurons by binding the N-methyl-D-aspartate receptor (N-methyl-D-aspartic acid, NMDA) and blocking glutamate. Like memantine (MEM), it is a low medium affinity, non-competitive NMDA receptor antagonist. The early study of the laboratory found that memantine can improve the depression-like symptoms in the depressed model rats and have a tendency to recover the damage to the water maze of the depressed model rats, and point out that it may be through the regulation of the NR2B receptor, and the partial recovery of the stress-induced synaptic plasticity in the stress rats. As a medicine for clinical application, the amantadine is similar to that of the memantine structure, but has the advantages of low price, clear side effect, good tolerance and long use history. Therefore, in this study, it will be mainly discussed whether the amantadine has the cognitive function damage of the depression model rats, and the possible mechanism of cytology and molecular biology. Male Wistar rats were randomly divided into four groups: control group (CON), AMA control group (CON + AMA), stress model group (STRESS) and AMA model group (STRESS + AMA). In the stress model group, the CUS model was used to simulate the behavior of the depression, and the experiment and weight change of the sugar water were used to verify the success of the model. The experiment of water maze mainly detects the memory function of the animal and the flexibility of the re-cognition. The long term potentiation (LTP) and de-gain (DP) of the hippocampal Schaffer side branch to CA1 were recorded by electrophysiology. The relative expression of the functional subunit NR2B and postsynaptic compact protein 95 (PSD-95) of the NMDA receptor in the hippocampus was detected by Western blot. The results of the main experiments were as follows: (1) The weight gain and the percentage of sugar water consumption in the STRESS group were significantly lower than that of the control group, and the amantadine significantly increased the weight gain of the rats in the stress model group and increased the percentage of sugar water consumption. (2) Compared with the normal control group, the escape latency of the STRESS group was significantly prolonged compared with the normal control group, and the amantadine significantly shortened the escape latency of the STRESS group rats. At the stage of spatial detection, the percentage of the target quadrant retention time and the number of platform-crossing times in the stress model group were significantly reduced, and the AMA was significantly increased after administration. (3) In the stage of space reverse training, the STRESS rats need more time to find the new position of the platform, and the amantadine significantly reduces the escape latency of the stress rats. in addition, that percentage of residence time of the new target quadrant and the number of platform traverse decreased significantly in the CON group in the STRESS group, and AMA significantly increased the number of platform crossing, and the target percentage of the new target quadrant increased without statistical difference. (4) Compared with the control group, the LTP in the CA1 region of the rats in the STRESS group was significantly reduced and the gain was significantly increased, and the LTP was significantly increased after the amantadine was given and the degain was significantly reduced. (5) The results of Western blot showed that the relative expression of NR2B and PSD-95 in the hippocampus of the rats was significantly lower than that of the CON group and the STRESS + AMA group. Based on the above results, we have the following conclusion: (1) The amantadine can effectively slow down the symptoms of the stress model, such as the lack of the pleasure, the weight loss, and the like, and show the potential antidepressant effect. (2) The potential mechanism of amantadine to decrease the degree of cognitive function injury in the depressed model rats may be to increase the relative expression of NR2B and PSD-95 in the hippocampus, thus preventing the two-way plastic imbalance of the LTP and de-gain of CA3-CA1, so that the spatial cognitive impairment of the depression model rats is reduced.
【學位授予單位】：南開大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R749.4
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