本文選題：藥物性耳聾 + 順鉑　； 參考：《遼寧中醫(yī)藥大學》2015年博士論文

【摘要】：第一部分順鉑腹腔注射誘導大鼠耳聾模型的實驗研究目的:探索順鉑腹腔注射誘導大鼠耳聾模型的最佳劑量及實驗條件。材料與方法:健康Wister大白鼠50只,雌雄各半,體重200±20g,6-8周齡。購于中國醫(yī)科大學實驗動物中心。將50只大鼠按照隨機數字法平均分為5組:空白對照組;模型1組;模型2組;模型3組;模型4組,每組10只。除空白對照組外,其余四組大鼠均經腹腔給予不同劑量的順鉑注射液注射,方法如下:空白對照組:每只大鼠給予生理鹽水注射液腹腔注射,劑量為1ml/100g·d-1,連續(xù)給藥5天。模型1組:每只大鼠給予0.4mg/ml濃度的順鉑注射液腹腔注射,劑量為0.5ml/100g·d-1,連續(xù)給藥5天(相當于2mg/Kg)。模型2組:每只大鼠給予0.8mg/ml濃度的順鉑注射液腹腔注射,劑量為0.5ml/100g·d-1,連續(xù)給藥5天(相當于4mg/Kg)。模型3組:每只大鼠給予1.6mg/ml濃度的順鉑注射液腹腔注射,劑量為0.5ml/100g·d-1,連續(xù)給藥5天(相當于8mg/Kg)。模型4組:每只大鼠給予3.2mg/ml濃度的順鉑注射液腹腔注射,劑量為0.5ml/100g·d-1,連續(xù)給藥5天(相當于16mg/Kg)。實驗結束后,對各組大鼠聽閾ABR閾值進行檢測,同時觀察耳蝸毛細胞的病理改變。結果:1.各組大鼠的一般狀態(tài)及死亡率空白對照組大鼠精神狀態(tài)良好,活動度正常,食水量正常,給予擊掌噪音刺激,耳廓反應靈敏。模型1組大鼠精神狀態(tài)較好,活動度略有減少,食水量正常,給予擊掌噪音刺激,耳廓反應較空白組反應略顯遲鈍,至實驗結束,未出現死亡大鼠。模型2、3、4組大鼠精神狀態(tài)較差,尤其3、4組,蜷縮于籠子角落,很少活動,食水量也明顯減少,模型4組大鼠在實驗的第4-5天幾乎沒有進食,給予擊掌噪音刺激,耳廓反應非常遲鈍,模型4組大鼠耳廓反應陰性。模型2組大鼠未見死亡情況出現,而模型3、4組大鼠出現死亡。模型3組于實驗第3天死亡1只、第5天死亡2只,總死亡率30%;模型4組于實驗第2天死亡1只、第3天死亡1只、第4天死亡1只,第5天死亡3只,總死亡率50%。2.各組大鼠ABR檢測結果各組大鼠ABR聽閾檢測結果顯示:與空白對照組大鼠比較,模型1、2、3、4組大鼠ABR閾值顯著升高(p0.01),有統計學差異。由模型1、2、3、4組組間比較結果可知,隨著順鉑注射劑量的加大,ABR閾值明顯升高。3.耳蝸基底膜毛細胞形態(tài)學觀察(1)耳蝸基底膜鋪片各組大鼠耳蝸基底膜鋪片結果顯示:空白對照組大鼠耳蝸基底膜鋪片清晰可見完整的三排毛細胞,排列均勻、整齊,無缺失及壞死細胞出現。模型1組大鼠基底膜鋪片上,明顯可見毛細胞缺失情況,但大部分排列仍然較為均勻整齊,僅偶見缺失。模型2組大鼠基底膜鋪片可見大面積形態(tài)模糊的毛細胞排列,大體形態(tài)排列仍較為整齊,模型3組和4組大鼠基底膜毛細胞形態(tài)喪失,無法辨認毛細胞形態(tài),偶見3-5個毛細胞輪廓排列在一起。(2)耳蝸病理各組大鼠耳蝸病理切片HE染色結果顯示:通過病理切片HE染色,可清晰的分辨耳蝸毛細胞形態(tài)及排列情況�？瞻讓φ战M大鼠耳蝸毛細胞排列整齊均勻,可見毛狀結構附著于基底膜上。模型1組大鼠耳蝸基底膜毛細胞排列均勻整齊,偶見缺失,但毛狀結構稀疏。模型2組大鼠耳蝸基底膜毛細胞缺失明顯,毛狀結構溶解。模型3組和4組大鼠耳蝸基底膜毛細胞缺失明顯,排列紊亂,幾乎見不到毛狀結構附著。結論:1.順鉑給予大鼠腹腔注射的方法,可導致大鼠ABR閾值的升高及耳蝸毛細胞的損傷。2.順鉑2mg/kg,日一次,連續(xù)5日給藥的劑量可導致大鼠耳蝸損傷,但不足以作為耳聾動物模型,用于科研實驗。3.順鉑8mg/kg和16mg/kg,日一次,連續(xù)5日給藥的劑量可導致大鼠耳蝸毛細胞過度損傷,不適合作為耳聾動物模型,用于科研實驗。4.順鉑4mg/kg,日一次,連續(xù)5日給藥的劑量可導致大鼠耳蝸損傷,損傷程度適中,模型穩(wěn)定,可作為耳聾動物模型,用于科研實驗。第二部分川芎嗪對順鉑誘導耳聾模型大鼠耳蝸毛細胞凋亡內部途徑干預機制的實驗研究目的:探索川芎嗪對順鉑誘導的耳聾模型大鼠耳蝸毛細胞凋亡早期內部途徑的干預作用和機制。材料與方法:將62只大鼠采用隨機數字法平均分為兩組,分別為:正常組(N組,11只),模型復制組(M組,51只)。正常組大鼠不做處理,正常飼養(yǎng);模型復制組大鼠采用順鉑腹腔注射的方法誘導藥物性耳聾模型。模型復制成功后,再次采用隨機數字法,將正常組大鼠隨機分成兩組:正常對照組(N1組)、川芎嗪對照組(N2組);將模型復制組大鼠隨機分為兩組:模型對照組(M1)、川芎嗪治療組(M2)。實驗第1-5天:正常組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射5天。模型復制組給予腹腔注射順鉑注射液,4mg/kg體重,連續(xù)注射5天。實驗第6-12天:正常對照組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射7天。川芎嗪對照組給予川芎嗪注射液腹腔注射,140mg/kg體重,連續(xù)注射7天。模型對照組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射7天。川芎嗪治療組給予川芎嗪注射液腹腔注射,140mg/kg體重,連續(xù)注射7天。末次給藥后1h,處死大鼠,剝離耳蝸組織,動存于-80℃冰箱中,用于p53、bax、bcl-2、caspase-9、caspase-3 m RNA及蛋白表達水平檢測。結果:1.模型評價結果模型復制后,N組和M組大鼠ABR檢測結果顯示:與正常組大鼠比較,模型復制組大鼠ABR閾值顯著升高(p0.01),有統計學意義。N組大鼠耳蝸基底膜毛細胞排列整齊,分布均勻,無明顯的細胞缺失情況;M組大鼠耳蝸基底膜毛細胞大部分變形,排列紊亂,可見大量溶解破壞的毛細胞,細胞間連接殘缺不全。2.各組大鼠耳蝸組織中p53、bax、bcl-2、caspase-9、caspase-3蛋白表達水平實驗結果顯示:與空白對照組比較,模型對照組及模型加川芎嗪組大鼠耳蝸組織中bax、p53、caspase-3、9蛋白表達水平顯著升高,而bcl-2蛋白表達水平顯著下降(p0.01);與模型對照組比較,模型加川芎嗪組大鼠耳蝸組織中bax、p53蛋白表達水平顯著降低,而bcl-2蛋白表達水平顯著升高(p0.01);空白對照組及空白加川芎嗪組組間比較,各指標均無顯著性差異(p0.05)。3.各組大鼠耳蝸組織中p53、bax、bcl-2、caspase-9、caspase-3 m RNA表達水平實驗結果顯示:與空白對照組比較,模型對照組及模型加川芎嗪組大鼠耳蝸組織中bax、p53、caspase-3、9 m RNA表達水平顯著升高,而bcl-2 m RNA表達水平顯著下降(p0.01);與模型對照組比較,模型加川芎嗪組大鼠耳蝸組織中bax、p53、caspase-3、9 m RNA表達水平顯著降低,而bcl-2 m RNA表達水平顯著升高(p0.01);空白對照組及空白加川芎嗪組組間比較,各指標均無顯著性差異(p0.05)。結論:1.給予大鼠順鉑腹腔注射(劑量4mg/kg),每日一次,連續(xù)5天,可成功誘導藥物性耳聾大鼠模型。2.川芎嗪可顯著下調模型大鼠耳蝸組織中的p53、bax、caspase-9、caspase-3 m RNA及蛋白表達水平,上調bcl-2 m RNA及蛋白表達水平。3.川芎嗪對藥物性耳聾模型大鼠耳蝸毛細胞的抗凋亡作用可能是通過阻斷或抑制細胞凋亡起始階段的內部途徑而實現的。第三部分川芎嗪對順鉑誘導耳聾模型大鼠耳蝸毛細胞凋亡外部途徑干預機制的實驗研究目的:探索川芎嗪對順鉑誘導的耳聾模型大鼠耳蝸毛細胞凋亡早期外部途徑的干預作用和機制。材料與方法:將62只大鼠采用隨機數字法平均分為兩組,分別為:正常組(N組,11只),模型復制組(M組,51只)。正常組大鼠不做處理,正常飼養(yǎng);模型復制組大鼠采用順鉑腹腔注射的方法誘導藥物性耳聾模型。模型復制成功后,再次采用隨機數字法,將正常組大鼠隨機分成兩組:正常對照組(N1組)、川芎嗪對照組(N2組);將模型復制組大鼠隨機分為兩組:模型對照組(M1)、川芎嗪治療組(M2)。實驗第1-5天:正常組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射5天。模型復制組給予腹腔注射順鉑注射液,4mg/kg體重,連續(xù)注射5天。實驗第6-12天:正常對照組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射7天。川芎嗪對照組給予川芎嗪注射液腹腔注射,140mg/kg體重,連續(xù)注射7天。模型對照組給予生理鹽水腹腔注射,5ml/kg體重,連續(xù)注射7天。川芎嗪治療組給予川芎嗪注射液腹腔注射,140mg/kg體重,連續(xù)注射7天。末次給藥后1h,處死大鼠,剝離耳蝸組織,動存于-80℃冰箱中,用于fas/fas L、caspase-8m RNA及蛋白表達水平檢測。結果:1.各組大鼠耳蝸組織中fas/fas L、caspase-8蛋白表達水平實驗結果顯示:與空白對照組比較,模型對照組及模型加川芎嗪組大鼠耳蝸組織中fas/fas L、caspase-8蛋白表達水平顯著升高(p0.01);與模型對照組比較,模型加川芎嗪組大鼠耳蝸組織中fas/fas L、caspase-8蛋白表達水平顯著降低(p0.01);空白對照組及空白加川芎嗪組組間比較,各指標均無顯著性差異(p0.05)。2.各組大鼠耳蝸組織中fas/fas L、caspase-8 m RNA表達水平實驗結果顯示:與空白對照組比較,模型對照組及模型加川芎嗪組大鼠耳蝸組織中fas/fas L、caspase-8 m RNA表達水平顯著升高(p0.01);與模型對照組比較,模型加川芎嗪組大鼠耳蝸組織中fas/fas L、caspase-8 m RNA表達水平顯著降低(p0.01);空白對照組及空白加川芎嗪組組間比較,各指標均無顯著性差異(p0.05)。結論:1.川芎嗪可顯著下調模型大鼠耳蝸組織中的fas/fas L、caspase-8 m RNA及蛋白表達水平。2.川芎嗪對藥物性耳聾模型大鼠耳蝸毛細胞的抗凋亡作用可能是通過阻斷或抑制細胞凋亡起始階段的外部途徑而實現的。
[Abstract]:The first part of the experimental study on induced deafness model of rats by intraperitoneal injection of cisplatin in order to explore the optimal dosage and experimental conditions of induced deafness model induced by intraperitoneal injection of cisplatin. Materials and methods: 50 healthy Wister rats, male and female, weight 200 + 20g, 6-8 weeks old, were bought at the experimental animal center of China Medical University. 50 rats were used in accordance with the experimental animal center. The random number method was divided into 5 groups: blank control group, model 1, model 2, model 3, model 4, 10 in each group. Except for blank control group, the other four groups of rats were injected with different doses of Cisplatin Injection intraperitoneally, the method was as follows: each rat was given intraperitoneal injection of saline injection, the dose of 1ml/100g. D-1, 5 days of continuous administration. Model 1: each rat was given an intraperitoneal injection of 0.4mg/ml concentration of Cisplatin Injection with a dose of 0.5ml/100g. D-1 for 5 days (equivalent to 2mg/Kg). Model 2: each rat was given an intraperitoneal injection of 0.8mg/ml concentration, the dose was 0.5ml/100g. D-1, and a continuous dose of 5 days (equivalent to 4mg/Kg). Model 3 groups: Each rat was given an intraperitoneal injection of 1.6mg/ml concentration of Cisplatin Injection, with a dose of 0.5ml/100g D-1, and a continuous dose of 5 days (equivalent to 8mg/Kg). Model 4: each rat was given a 3.2mg/ml concentration of Cisplatin Injection intraperitoneal, a dose of 0.5ml/100g D-1, and a continuous dose of 5 days (equivalent to 16mg/Kg). At the end of the experiment, the threshold ABR threshold of rats in each group was completed. The values were detected and the pathological changes of the cochlear hair cells were observed at the same time. Results: 1. the general state and death rate of the rats in each group were in good mental state, normal activity, normal water intake, irritation of the noise of the palm, and the sensitive auricle reaction. The 1 groups of rats in the model were better, the activity degree was slightly reduced and the water content was normal. With the stimulation of the noise, the response of the auricle was slightly slower than that in the blank group. To the end of the experiment, there was no death in the rat. The model 2,3,4 group had a poor mental state, especially in the 3,4 group, curled up in the corner of the cage, with little activity and a significant decrease in the amount of water. The 4 rats in the model group had almost no feeding on the 4-5 day of actual test, giving the ear noise stimulation, ear irritation. The auricle reaction was very slow in the model 4 rats. There was no death in the model group of rats. There was no death in the model 2 rats, but the model 3,4 group died. The model 3 groups died 1 in the third day experiment and 2 in fifth days, the total mortality was 30%. The model 4 group died second days, 1, third days death, and total death The result of ABR hearing threshold detection in each group of rats in each group was 50%.2.. The results of ABR hearing threshold of rats in each group showed that compared with the blank control group, the ABR threshold of the model 1,2,3,4 group increased significantly (P0.01), and there was a statistical difference. The results of the model 1,2,3,4 group showed that with the increase of the injection dose of cisplatin, the threshold of ABR increased significantly in the.3. cochlear base. Morphological observation of membrane hair cell (1) the result of the laying of the cochlear basement membrane in the cochlear basement membrane sheets showed that the complete three rows of hair cells were clearly visible in the basal membrane of the rats in the blank control group, and the arrangement was uniform and tidy, and the absence of the missing and necrotic cells appeared. The loss of hair cells in the basal membrane of the 1 groups of rats was obviously visible, but the loss of hair cells was obvious. Most of the permutations were still even and neatly, only missing. The 2 groups of rats in the base membrane of the model group showed a large area of fuzzy hair cells arranged in large area. The morphology of the basal membrane of the model 3 and the 4 groups of rats lost the form of hair cells in the basement membrane, and the outline of 3-5 hair cells could not be identified. (2) ears (2). The HE staining results of the cochlear pathological sections of the rats in each group showed that the morphology and arrangement of the cochlear hair cells could be clearly identified by pathological section HE staining. The hair cells of the cochlear hair cells in the blank control group were arranged neatly and evenly, and the hair like structure attached to the basement membrane. The 1 groups of rat cochlear basal membrane hair cells were arranged evenly and neatly. The loss of hair like structure was sparse. The loss of hair cells in the basal membrane of the cochlea of model 2 rats was obvious, and the hair like structure dissolved. The 3 groups and 4 groups of rat cochlea basal membrane hairy cells were lost obviously, the arrangement was disorderly, and almost no hairy structure attached. Conclusion: 1. the method of intraperitoneal injection of cisplatin in rats can lead to the increase of ABR threshold and ear of rats. The damage of the cochlear cells is.2. cisplatin 2mg/kg. Once a day, the dose of 5 days of continuous administration can cause cochlear injury in rats, but it is not enough to be used as an animal model of deafness. It is used for research and experiment.3. cisplatin 8mg/kg and 16mg/kg. On the other day, the dose of 5 days of continuous administration can lead to excessive damage of the rat cochlear capillary cell, which is not suitable to be used as a deafness animal model. Research experiment.4. cisplatin 4mg/kg, once a day, the dose of 5 days continuous administration can lead to cochlear injury in rats, the degree of injury is moderate, the model is stable, and it can be used as a deafness animal model and used in scientific research. The second part of the experimental study on the intervention mechanism of Ligustrazine on the internal pathway of cochlear hair cell withering in the deafness model rats induced by cisplatin The effect and mechanism of Ligustrazine on the early internal pathway of cochlear hair cell apoptosis induced by cisplatin in the deafness model of cisplatin. Materials and methods: 62 rats were divided into two groups by random number method: normal group (group N, 11), model replicating group (group M, 51). Normal rats were not treated, normal rearing, model replicating group was large. The rat model of deafness was induced by intraperitoneal injection of cisplatin. After the model replication was successful, the rats were randomly divided into two groups: normal control group (group N1) and ligustrazine control group (group N2). The model replicas group was randomly divided into two groups: model control group (M1), ligustrazine treatment group (M2). Experiment 1-5 Day: normal group was given intraperitoneal injection of saline, 5ml/kg weight, continuous injection for 5 days. Model replicating group was given intraperitoneal injection of Cisplatin Injection, 4mg/kg weight, continuous injection for 5 days. On day 6-12: normal control group was given intraperitoneal injection of saline, 5ml/kg weight, continuous injection for 7 days. Ligustrazine control group was given intraperitoneal injection of ligustrazine injection. Injection, 140mg/kg weight, continuous injection for 7 days. The model control group was given intraperitoneal injection of saline, 5ml/kg weight, continuous injection for 7 days. Ligustrazine treatment group was given intraperitoneal injection of ligustrazine injection, 140mg/kg weight, continuous injection for 7 days. After the last dose of 1H, the rats were killed and cochlear tissue was stripped at -80 centigrade refrigerator and used for p53, Bax, Bcl-2, CASPA. Se-9, caspase-3 m RNA and protein expression level detection. Results: after the 1. model evaluation model was replicated, the results of ABR detection in N and M group rats showed that the ABR threshold of the model replicas rats increased significantly (P0.01), and there was statistical significance in the.N group of the rat cochlea basal membrane hair cells arranged neatly and evenly distributed, without obvious finer. In the M group, most of the rat cochlear basal membrane hair cells were deformed and arranged in disorder. A large number of dissolving and damaged hair cells were seen, and the intercellular connection was incomplete in the cochlear tissues of.2. rats. The experimental results of p53, Bax, Bcl-2, caspase-9, and caspase-3 protein expression in the rat cochlear tissues were shown: compared with the blank control group, the model control group and the model plus Sichuan were compared with the blank control group. The expression level of Bax, p53, caspase-3,9 protein in the cochlear tissue of the Ligustrazine group increased significantly, while the expression level of Bcl-2 protein decreased significantly (P0.01). Compared with the model control group, the expression level of Bax, p53 protein in the rat cochlear tissue of Ligustrazine group was significantly decreased, and the level of Bcl-2 protein expression was significantly increased (P0.01), and the blank control group and the empty space were empty. The results of p53, Bax, Bcl-2, caspase-9, caspase-3 m RNA expression in the cochlear tissues of rats in each group of.3. groups showed no significant difference (P0.05) in the cochlear tissue of each group. The results showed that the level of Bax, p53, caspase-3,9, in the model control group and the model plus Ligustrazine group were significantly higher than that in the control group. The expression level of Bcl-2 m RNA decreased significantly (P0.01). Compared with the model control group, the RNA expression level of Bax, p53, caspase-3,9 m in the rat cochlear tissue of the model tetramethylpyrazine group decreased significantly, while the Bcl-2 m RNA expression level increased significantly, and there was no significant difference in the indexes between the blank control group and the blank and ligustrazine group. 05). Conclusion: 1. intraperitoneal injection of cisplatin (dose 4mg/kg), once a day for 5 days, can successfully induce.2. tetramethylpyrazine in the rat model of drug-induced deafness, which can significantly reduce the level of p53, Bax, caspase-9, caspase-3 m RNA and protein expression in the rat cochlear tissue of model rats, up Bcl-2 m RNA and protein expression level.3. tetramethylpyrazine on drug sex The anti apoptosis effect of the cochlear hair cells in the deafness model rats may be realized by blocking or inhibiting the internal pathway of the initial stage of apoptosis. Third experimental study on the mechanism of the intervention mechanism of the external pathway of the apoptosis of the cochlear hair cells induced by cisplatin in the deafness model of the rat: explore the deafness model induced by TMP The intervention and mechanism of the early external pathway of the rat cochlear hair cell apoptosis. Materials and methods: 62 rats were divided into two groups by random number method, the normal group (group N, 11), model replicating group (group M, 51). The normal group rats were not treated, and the rats in the model replicating group were induced by cisplatin intraperitoneal injection. After the model replication was successful, the normal group rats were randomly divided into two groups: normal control group (group N1) and ligustrazine control group (group N2). The model replicating group was randomly divided into two groups: model control group (M1), tmw treatment group (M2). The normal group was given intraperitoneal injection of saline. Injection, 5ml/kg weight, continuous injection for 5 days. The model replicating group was given intraperitoneal injection of Cisplatin Injection and 4mg/kg body weight for 5 days. On day 6-12: normal control group was given intraperitoneal injection of saline, 5ml/kg weight, continuous injection for 7 days. Ligustrazine control group was given intraperitoneal injection of ligustrazine injection, 140mg/kg weight, continuous injection for 7 days. The control group was given intraperitoneal injection of saline, 5ml/kg weight, continuous injection for 7 days. Ligustrazine treatment group was given intraperitoneal injection of ligustrazine injection, 140mg/kg weight, continuous injection for 7 days. After the last administration, 1H, rats were killed and cochlear tissue was stripped at -80 C refrigerator and used for the detection of fas/fas L, caspase-8m RNA and protein expression level. Results: 1. The experimental results of fas/fas L and caspase-8 protein expression in the cochlear tissues of rats in each group showed that: compared with the blank control group, the level of fas/fas L and caspase-8 protein expression in the rat cochlear tissues of the model control group and the model Ligustrazine group increased significantly (P0.01). Compared with the model control group, the model plus Ligustrazine group had fas/fas in the cochlear tissue of the Ligustrazine group. L, Caspase-8 protein expression level was significantly decreased (P0.01), and there was no significant difference between the blank control group and the blank Kagawa group (P0.05) the fas/fas L in the cochlear tissue of each group of.2. rats, the experimental results of the caspase-8 m RNA expression showed that the model control group and the model plus Ligustrazine group were compared with the blank group. The expression level of fas/fas L and caspase-8 m RNA in the worm tissues was significantly higher (P0.01). Compared with the model control group, the expression level of fas/fas L and caspase-8 m RNA in the rat cochlear tissue of the model plus Ligustrazine group was significantly lower (P0.01), and there was no significant difference between the blank control group and the blank Kagawa group. Conclusion: 1. Ligusticum chuanxiong. The anti apoptosis effect of fas/fas L, Caspase-8 m RNA and protein expression level.2. tetramethylpyrazine on the cochlear hair cells of drug-induced deafness model rats may be achieved by blocking or inhibiting the external pathway of the initial stage of apoptosis.
【學位授予單位】：遼寧中醫(yī)藥大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R965

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