本文選題：Colivelin + β淀粉樣蛋白��； 參考：《山西醫(yī)科大學》2012年碩士論文

【摘要】：阿爾茨海默�。ˋlzheimer’s disease, AD）是一種原發(fā)性中樞神經(jīng)系統(tǒng)退行性疾病，其主要臨床表現(xiàn)為進行性認知功能障礙、學習和記憶能力喪失、智力下降，晚期出現(xiàn)嚴重癡呆。目前，全世界約有3600萬AD患者，據(jù)ADI估計這個數(shù)字以每20年翻一倍的速度增長,到2030年將會達到6600萬人。我國AD患者目前超過500萬，并且隨著人口老齡化速度和程度的加劇，我國AD的發(fā)病率和患者總數(shù)還將持續(xù)增加。毫無疑問，AD已成為21世紀威脅人類的最嚴重疾病之一，是繼心血管疾病、腦血管疾病和癌癥之后嚴重影響老年人身體健康和人類壽命的“第四大殺手”。 AD典型病理特征之一是腦內(nèi)出現(xiàn)高密度的老年斑。研究表明，老年斑的主要成分是由39-43個氨基酸組成的淀粉樣β蛋白（Amyloidβ-protein，Aβ）。全長Aβ片段的神經(jīng)毒性作用已有廣泛報道，在此基礎之上，有大量實驗表明Aβ25-35是全長Aβ分子中一個較短的活性片段。本研究室在以往的研究中也發(fā)現(xiàn)，Aβ25-35能在細胞培養(yǎng)、離體膜片鉗和在體電生理實驗中表現(xiàn)出與全長Aβ類似的神經(jīng)毒性作用。這些研究提示，拮抗Aβ神經(jīng)毒性作用可能是治療AD的一個有效手段。然而，迄今為止針對Aβ的AD治療尤其是有效拮抗Aβ神經(jīng)毒性作用的藥物研究，仍然沒有突破性進展。 Humanin（HN）是日本學者于2001年首次發(fā)現(xiàn)的一個由24個氨基酸組成的線性多肽，能夠特異性抑制AD及其各種相關損傷引起的神經(jīng)元細胞死亡。Colivelin是由日本學者于2005年首次報道的一種新的、由26個氨基酸組成的HN衍生物。目前有部分研究顯示，Colivelin有很強的神經(jīng)保護作用，能夠有效逆轉(zhuǎn)Aβ在原代培養(yǎng)皮層神經(jīng)元和行為學實驗中表現(xiàn)出的神經(jīng)毒性。然而，對于Colivelin在整體動物中的作用，尤其是對學習記憶的電生理模型長時程增強（long-term potentiation, LTP）的影響及Colivelin保護作用的機制的研究還處于起步階段。 Morris水迷宮（Morris water maze, MWM）是用來衡量動物學習記憶功能的經(jīng)典的行為學實驗手段，能夠有效反映動物的認知功能改變，因而被廣泛應用于動物學習記憶功能包括AD動物行為學測試研究。長時程增強(long term potentiation, LTP)是由高頻刺激(high-frequency stimulus, HFS)所引發(fā)的一種興奮性突觸傳遞效能長時間持續(xù)增強的現(xiàn)象。鑒于海馬是AD發(fā)病過程中最早和最易受累的腦區(qū)之一，且海馬LTP的傷害與動物認知缺損高度相關，海馬LTP特別是在體LTP已被視為研究學習記憶和AD發(fā)病機制的一個重要的電生理細胞模型而受到普遍關注。 因此，本實驗采用海馬內(nèi)分別給予Aβ25-35、生理鹽水、Colivelin（0.2 nmol）和Colivelin（0.2 pmol、2 pmol、0.2 nmol）+Aβ25-35的方法，觀察了Colivelin對大鼠學習記憶的影響，并探討其對于Aβ25-35導致的學習記憶功能損傷的逆轉(zhuǎn)作用。實驗研究分為以下兩部分：（1）利用國際公認的經(jīng)典的Morris水迷宮測試手段，觀察Colivelin預處理是否能有效拮抗大鼠Aβ所致的學習記憶傷害；（2）利用在體海馬LTP記錄手段，觀察海馬內(nèi)注射Colivelin預處理對于Aβ25-35引起的LTP壓抑的作用，進一步闡明Colivelin神經(jīng)保護作用的突觸前、后機制。通過以上兩部分研究，為Colivelin參與神經(jīng)系統(tǒng)功能調(diào)節(jié)提供充分的實驗證據(jù)，從而為保護神經(jīng)元免受Aβ神經(jīng)毒性傷害，為預防和治療AD提供新的思路和理論依據(jù)。 第一部分：Colivelin部分逆轉(zhuǎn)Aβ25-35引起的大鼠空間學習記憶功能損害 目的：利用Morris水迷宮測定大鼠空間學習記憶功能，觀察海馬內(nèi)給予Aβ25-35、生理鹽水、Colivelin以及合用Colivelin和Aβ25-35后大鼠在Morris水迷宮中的行為學表現(xiàn)，探討Colivelin預處理對Aβ引起的空間學習記憶功能損傷可能的作用。 方法：取運動靈活、無視力障礙的成年雄性SD大鼠(200-230g)隨機分組，進行Morris水迷宮定位航行和空間探索實驗，分別測定大鼠的空間學習和記憶能力。主要指標包括大鼠尋找平臺的平均逃避潛伏期和游泳距離、撤離平臺后大鼠在目標象限游泳時間（限定時間為：120秒）和距離。同時，測定各組大鼠的游泳速度及大鼠的視力，以排除運動能力與視力障礙對測定指標的影響。各種藥物均經(jīng)海馬內(nèi)注射給予，恢復2-3周后進行實驗。 結(jié)果：（1）對照組大鼠學習記憶功能正常。逃避潛伏期在訓練第1-5天內(nèi)分別為79.0±3.3 s, 36.6±3.0 s, 20.2±2.0 s, 19.9±1.3 s和16.5±1.7 s；大鼠找到平臺所游過的距離分別為1427.5±135.1 cm, 689.4±80.8 cm, 369.2±50.7 cm, 322.4±40.6 cm和265.3±44.0 cm；撤除平臺后大鼠在目標象限游泳所用時間和距離分別為55.4±3.0s和1150.4±63.9cm。（2）海馬內(nèi)注射4nmol Aβ25-35后顯著降低了大鼠的空間學習和記憶能力。Aβ25-35海馬內(nèi)注射組大鼠的平均潛伏期和游過距離在第1天與對照組沒有明顯差別，在第2-5天分別為52.8±4.3 s, 39.5±1.6 s, 29.3±2.6 s, 26.8±1.4 s和899.1±108.9 cm, 551.7±54.9 cm,448.5±68.7 cm, 369.6±28.6 cm，與對照組相比，其平均潛伏期明顯延長，游過距離明顯縮短（P0.01或P0.05）；撤除平臺后大鼠在目標象限游泳所占時間和距離顯著縮短，分別為36.8±2.9 s和756.9±52.9 cm（P0.01）。（3）海馬內(nèi)單獨注射0.2 nmol Colivelin后，大鼠的學習、記憶功能與對照組相比均未受到影響（P0.01），分別為35.3±4.4 s,22.1±2.9 s, 21.4±2.6 s, 19.4±0.7 s和670.0±90.6 cm, 398.3±80.9 cm, 357.2±51.5 cm,260.0±37.0 cm，撤掉平臺后在目標象限游泳所用的時間和距離為55.0±3.0 s和1148±63.1cm，與對照組相比無明顯差別（P0.01）。但聯(lián)合給予Colivelin（0.2 pmol,2 pmol,0.2nmol）與Aβ25-35后，與Aβ25-35組相比，各組平均潛伏期和游過距離兩個指標在第2-5天都有縮短現(xiàn)象，0.2 pmol Colivelin+ Aβ25-35組(n=11)2-5天找到平臺所用的時間和距離分別為45.4±3.5 s, 33.9±1.7 s, 24.6±3.8 s, 22.3±1.9 s和728.0±78.3 cm, 425.1±43.8 cm,339.9±84.4 cm, 286.1±41.5 cm；在2 pmol Colivelin+ Aβ25-35組(n=12)分別為33.8±3.8 s,29.8±2.1 s, 22.0±1.6 s, 20.0±1.6 s和582.1±115.2 cm, 385.6±59.1 cm, 281.5±33.3 cm,228.8±27.3 cm；在0.2 nmol Colivelin+ Aβ25-35組(n=12),分別為28.1±2.4 s, 20.8±2.1 s,19.3±1.6 s, 17.9±2.4 s和509.5±63.6 cm,302.9±56.7 cm, 247.9±28.8 cm, 203.8±47.9 cm與Aβ25-35組相比均有明顯縮短（P0.01），并且這種逆轉(zhuǎn)作用具有劑量依賴性。撤除平臺后大鼠在目標象限游泳所用時間和距離實驗中，0.2 pmol Colivelin+ Aβ25-35組為39.1±2.1s和799.0±74.0 cm；2 pmol Colivelin+ Aβ25-35組為43.8±3.0 s和934.9±53.8 cm；0.2nmol Colivelin+ Aβ25-35組為54.0±3.7 s和1148.4±63.0 cm，與Aβ25-35組相比均有并不同程度的增加，并且這種增加呈現(xiàn)出劑量依賴性。（4）各實驗組動物在可視平臺實驗中的逃避潛伏期和游泳速度均無顯著區(qū)別。 結(jié)論：海馬內(nèi)注射Aβ25-35能夠傷害大鼠空間學習和記憶能力，單獨使用Colivelin不會對大鼠的學習和記憶活動造成影響，但Colivelin預處理之后給予Aβ25-35，，發(fā)現(xiàn)Colivelin可部分逆轉(zhuǎn)Aβ對大鼠空間學習記憶功能的損傷作用，并且此逆轉(zhuǎn)作用具有劑量依賴性。 第二部分: Colivelin拮抗Aβ25-35引起的大鼠在體海馬LTP損害 目的：通過海馬內(nèi)注射Colivelin以及Aβ25-35后記錄海馬場興奮性突觸后電位（field excitatory postsynaptic potentials, fEPSPs）和長時程增強（LTP），研究不同劑量Colivelin預處理之后對Aβ25-35壓抑大鼠海馬CA1區(qū)在體LTP的逆轉(zhuǎn)作用及其可能機制。 方法：采用海馬內(nèi)注射給藥后已行水迷宮測試的SD大鼠，麻醉后將其固定在腦立體定位儀上，將綁定好的刺激電極和記錄電極精確插入到海馬刺激和記錄部位。通過給予海馬Schaffer側(cè)枝單個電刺激、強直電刺激和雙脈沖刺激，在海馬CA1區(qū)放射層誘發(fā)和記錄基礎的fEPSPs、強直刺激引起的LTP，以及配對脈沖引起的雙脈沖易化（pairedpulse facilitation, PPF）。 結(jié)果：（1）Aβ25-35不影響基礎性突觸傳遞，但對于高頻刺激引起的LTP具有明顯的壓抑作用。給予HFS后0 min,30 min,60 min，對照組fEPSPs幅度增強至176.8±4.1%,150.6±2.8%和141.3±2.3%；4 nmol Aβ25-35組的fEPSPs幅度分別只有166.6±3.0%,116.2±1.6和106.2±2.8%；表明Aβ25-35片段可明顯壓抑海馬CA1區(qū)LTP (P0.01)（2）單獨給予0.2 nmol Colivelin后，基礎性突觸傳遞和LTP都沒有發(fā)生明顯改變。其在給予HFS后0 min,30 min,60 min時分別為：178.5±2.9%，139.9±2.9%，138.5±2.1%。給予Colivelin(0.2 pmol,2 pmol,0.2 nmol)預處理后，再給予Aβ25-35，在0.2 pmol Colivelin+Aβ25-35組，其數(shù)值分為為：164.5±1.8%，122.4±1.9%，110.3±1.1%；在2 pmolColivelin+ Aβ25-35組中，數(shù)值分別為：166.0±2.3%，132.2±2.1%，119.2±1.2%；在0.2nmol Colivelin+ Aβ25-35組中則分別為：178.7±2.8%，139.8±2.4%，126.0±2.6%。LTP值在HFS后0 min, 30 min和60 min時的數(shù)值均高于單獨給予Aβ25-35 LTP (P0.01)，并且差別具有劑量依賴性。表明Colivelin能夠劑量依賴性的逆轉(zhuǎn)Aβ對LTP的傷害作用。（3）對照組和各實驗組的PPF都沒有顯著差異，提示所用各種藥物影響LTP主要不是通過突觸前機制實現(xiàn)的。 結(jié)論：海馬內(nèi)注射Aβ25-35能夠壓抑大鼠海馬在體LTP；單獨使用Colivelin不會對海馬的基礎性傳遞功能及LTP造成影響，但是先于Aβ25-35預處理可以部分改善Aβ25-35對LTP的壓抑作用，并且這種作用具有劑量依賴性。 總之，本研究分別利用Morris水迷宮和LTP兩種實驗方法，證明了Colivelin可有效對抗Aβ所致的行為學和海馬LTP的傷害。因此，本研究為AD的預防和治療提供了一個新的線索和思路。
[Abstract]:Alzheimer 's disease (AD) is a primary neurodegenerative disease of the central nervous system. Its main clinical manifestations are progressive cognitive impairment, loss of learning and memory, loss of intelligence, and advanced dementia. At present, about 36 million AD patients worldwide, according to ADI, have doubled the number to double every 20 years. The rate of growth will reach 66 million in 2030. The AD patients in China are now more than 5 million, and with the increasing speed and degree of population aging, the incidence of AD and the total number of patients in China will continue to increase. There is no doubt that AD has become one of the most serious diseases that threaten human beings in twenty-first Century, which is followed by cardiovascular disease, cerebrovascular disease and After cancer, the "fourth killer" seriously affects the health and life span of the elderly.
One of the typical pathological features of AD is the high density of the senile plaques in the brain. Studies have shown that the main component of the senile plaques is Amyloid beta -protein (A beta), which consists of 39-43 amino acids. The neurotoxicity of the full length A beta fragment has been widely reported. On this basis, a large number of experiments have shown that A beta 25-35 is the full length of the A beta molecule. A shorter active fragment. In previous studies, this study also found that A beta 25-35 showed neurotoxicity similar to full-length A beta in cell culture, in vitro patch clamp and in body electrophysiological experiments. These studies suggest that antagonism to the neurotoxicity of A beta may be an effective means for the treatment of AD. There is still no breakthrough in the study of A beta AD therapy, especially for the effective anti A beta neurotoxicity.
Humanin (HN) is a linear polypeptide composed of 24 amino acids for the first time in 2001 by Japanese scholars. It is a new type of HN derivative, composed of 26 amino acids, which was first reported by Japanese scholars in 2005 by Japanese scholars in 2005. It is a new kind of HN derivative, which is first reported by Japanese scholars in 2005. It shows that Colivelin has a strong neuroprotective effect and can effectively reverse the neurotoxicity of A beta in primary cultured cortical neurons and behavioural experiments. However, the effect of Colivelin on the whole animal, especially the effect of long-term potentiation (LTP) on the electrophysiological model of learning and memory, and Colivel The mechanism of in protection is still in its infancy.
The Morris water maze (Morris water maze (MWM)) is a classic behavioral experiment used to measure the learning and memory function of animals. It can effectively reflect the changes in cognitive function of animals. Therefore, it is widely used in animal learning and memory function, including the study of AD animal behavior test. Long term enhancement (long term potentiation, LTP) is a high frequency (long term potentiation, LTP). High-frequency stimulus (HFS) triggering a prolonged and continuous enhancement of the efficiency of excitatory synaptic transmission. Given that the hippocampus is one of the earliest and most vulnerable brain regions in the AD pathogenesis, and the damage of the hippocampus LTP is highly related to the cognitive impairment of animals, and the hippocampus LTP, especially in the body LTP, has been considered to study learning memory and AD. The pathogenesis of an important electrophysiological cell model has attracted widespread attention.
Therefore, in this experiment, A beta 25-35, saline, Colivelin (0.2 nmol) and Colivelin (0.2 pmol, 2 pmol, 0.2 nmol) +A beta 25-35 were used to observe the effect of Colivelin on learning and memory in rats and to explore the reversal effect of A beta 25-35 on the impairment of learning and memory function. The experimental study was divided into two parts. (1) using the internationally recognized classic Morris water maze test to observe whether Colivelin preconditioning can effectively antagonize the learning and memory injury caused by A beta in rats; (2) to observe the effect of Colivelin preconditioning on A beta 25-35 induced by A beta 25-35 in hippocampal LTP recording, and to further clarify Colivelin neuroprotection. Through the above two parts, we provide sufficient experimental evidence for the involvement of Colivelin in the function regulation of the nervous system, thus providing a new idea and theoretical basis for the protection of neurons from A beta neurotoxicity and for the prevention and treatment of AD.
Part one: Colivelin partially reverses the impairment of spatial learning and memory induced by A beta 25-35 in rats.
Objective: to determine the spatial learning and memory function of rats by Morris water maze, and observe the behavior of A beta 25-35, saline, Colivelin, and Colivelin and A beta 25-35 rats in the Morris water maze, and explore the possible effect of Colivelin preconditioning on the impairment of spatial learning and memory impairment induced by A beta.
Methods: the adult male SD rats (200-230g) without visual impairment were randomly divided into the Morris water maze navigation and space exploration experiment. The spatial learning and memory ability of the rats were measured respectively. The main indexes included the average escape latency and swimming distance of the rats in search of the platform. The rats were in the target image after the evacuation platform. Swimming time limited (120 seconds) and distance were limited. At the same time, the swimming speed of rats and the visual acuity of rats were measured in order to exclude the influence of motor ability and visual impairment on the measurement index. All kinds of drugs were given by intramuscular injection in the hippocampus, and the experiment was carried out after 2-3 weeks.
Results: (1) the learning and memory function of the control group was normal. The escape latency was 79 + 3.3 s, 36.6 + 3 s, 20.2 + 2 s, 19.9 + 1.3 s and 16.5 + 1.7 s, respectively. The time and distance of the rats in the target quadrant swimming were 55.4 + 3.0s and 1150.4 + 63.9cm. (2) intramuscular injection of 4nmol A beta 25-35. The average latency and distance of the rats in the group of intramuscular injection of.A beta 25-35 were not significantly different from those in the control group at the 2-5 day on the 2-5 day. They were 52.8 + 4.3 s, 39.5 + 1.6 s, 29.3 + 2.6 s, 26.8 + 1.4 s and 899.1 + 108.9 cm, 551.7 + 54.9 cm, 448.5 + 39.5 cm. Compared with the control group, the average latency period was obviously prolonged and the travel distance was obviously shortened (P0.01 or P0.05). After the removal of the platform, the rats in the target quadrant swimming time and distance were significantly shortened, respectively. For 36.8 + 2.9 s and 756.9 + 52.9 cm (P0.01). (3) a single injection of 0.2 nmol Colivelin in the hippocampus, the learning and memory function of the rats were not affected by the control group (P0.01), respectively 35.3 + 4.4 s, 22.1 + 2.9 s, 21.4 + 2.6 s, 19.4 + s and cm cm. The time and distance of the target quadrant swimming were 55 + 3 s and 1148 + 63.1cm, and there was no significant difference compared with the control group (P0.01). However, compared with the A beta 25-35 group with Colivelin (0.2 pmol, 2 pmol, 0.2nmol) and A beta 25-35, the average latency and the travel distance two indexes were shortened on the 2-5 day, 0.2 pmol Colivelin+ A. The time and distance to find the platform for the 2-5 days of group n=11 (n=11) were 45.4 + 3.5 s, 33.9 + 1.7 s, 24.6 + 3.8 s, 22.3 + 1.9 s and 728 + 78.3 cm, 425.1 + cm and cm, respectively. 385.6 + 59.1 cm, 281.5 + 33.3 cm, 228.8 + 27.3 cm, 0.2 nmol Colivelin+ A beta 25-35 (n=12), 28.1 + 2.4 s, 20.8 + 2.1 s and 19.3 + s respectively. After the removal of the platform, the 0.2 pmol Colivelin+ A beta 25-35 groups were 39.1 + 2.1S and 799 + 74 cm, and 2 pmol Colivelin+ A beta 25-35 groups were 43.8 + 3 s and 934.9 + 25-35 cm. The increase in different degrees and this increase showed a dose dependence. (4) there was no significant difference between the escape latency and the swimming speed of the experimental groups in the visual platform experiment.
Conclusion: intramuscular injection of A beta 25-35 can harm the spatial learning and memory ability of rats. The use of Colivelin alone can not affect the learning and memory activities of rats, but A beta 25-35 is given after Colivelin preconditioning. It is found that Colivelin can partly reverse the damage effect of A beta on the spatial learning and memory function of rats, and this reversal effect is also found. There is a dose-dependent manner.
The second part: Colivelin antagonize the LTP damage induced by A beta 25-35 in the hippocampus of rats.
Objective: to record the excitatory postsynaptic potential (field excitatory postsynaptic potentials, fEPSPs) and long term potentiation (LTP) in hippocampal field after injection of Colivelin and A beta 25-35 in the hippocampus, and to study the reversal effect and possible mechanism of the CA1 region of hippocampus in the CA1 region of A beta 25-35 in rats after different doses of Colivelin preconditioning.
Methods: SD rats were tested with water maze test after intralanhippocampal injection. After anesthesia, they were fixed on the stereotactic brain locator. The binding stimulation electrode and recording electrode were inserted into the hippocampus stimulation and recording site accurately. By giving a single electrical stimulation to the hippocampal Schaffer side branch, direct electrical stimulation and double pulse stimulation, in the hippocampal CA1 The radiation layer induces and records basal fEPSPs, LTP induced by tetanic stimulation, and pairedpulse facilitation (PPF) induced by paired pulses.
Results: (1) A beta 25-35 did not affect the basic synaptic transmission, but it had a significant inhibition effect on LTP induced by high frequency stimulation. After HFS, 0 min, 30 min, 60 min were given, and the fEPSPs amplitude in the control group was increased to 176.8 + 4.1%, 150.6 + 2.8% and 141.3 +, and the fEPSPs amplitude of 4 nmol A beta 25-35 groups was only 0. The results showed that the A beta 25-35 fragment could obviously suppress the LTP (P0.01) (P0.01) (2) of the hippocampal region (P0.01) (2) to be given to 0.2 nmol Colivelin alone. The basic synaptic transmission and LTP had not changed obviously. It was 178.5 + 2.9%, 139.9 + 2.9%, 138.5 + 2.1%, respectively, after giving HFS, after giving HFS, 139.9 + 2.9%, 138.5 + 2.1%. The value of A beta 25-35, in the 0.2 pmol Colivelin+A beta 25-35 groups, is divided into 164.5 + 1.8%, 122.4 + 1.9%, 110.3 + 1.1%, and in the 2 pmolColivelin+ A beta group 25-35, the values are respectively 166 + 2.3%, 132.2 + 122.4, respectively. The values of min, 30 min and 60 min were higher than that of A beta 25-35 LTP (P0.01) alone, and the difference was dose-dependent. It showed that Colivelin could reverse the dose dependence of A beta against LTP. (3) there was no significant difference between the control group and the PPF of the experimental groups, suggesting that the effects of all kinds of drugs on LTP were not through the presynaptic machine. The system is realized.
Conclusion: intramuscular injection of A beta 25-35 can inhibit the LTP in the hippocampus of rats. The use of Colivelin alone will not affect the basic transfer function of the hippocampus and LTP, but the preconditioning before A beta 25-35 can partly improve the inhibitory effect of A beta 25-35 on LTP, and this effect is dependent on the dose of dose.
In conclusion, this study uses two experimental methods, Morris water maze and LTP, to prove that Colivelin can effectively antagonize the behavior of A beta and the injury of LTP in the hippocampus. Therefore, this study provides a new clue and idea for the prevention and treatment of AD.

【學位授予單位】：山西醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R749.16

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