【摘要】： 研究背景和目的：慶大霉素是一種臨床應(yīng)用較為普遍的氨基糖甙類抗生素,其耳毒性所致的感音神經(jīng)性聾較為常見,但其耳毒性機(jī)理尚不清楚,目前尚無理想的方法進(jìn)行預(yù)防。本課題通過構(gòu)建慶大霉素致聾大鼠模型,觀察慶大霉素致耳毒性過程中耳蝸基底膜毛細(xì)胞的形態(tài)變化情況,耳蝸外側(cè)壁血管紋毛細(xì)血管網(wǎng)的病理改變及ET-A的表達(dá)變化情況,以研究慶大霉素耳毒性的可能機(jī)制,并進(jìn)一步探討阿魏酸鈉對慶大霉素耳毒性的保護(hù)作用,從而尋求降低慶大霉素耳毒性的方法。 研究方法：將32只Wistar大鼠隨機(jī)分成三組：對照組(n=8只)、慶大霉素組(n=13只,150 mg／kg肌注7天)、慶大霉素(150 mg／kg肌注7天)和阿魏酸鈉(50 mg／kg肌注7天)聯(lián)合用藥組(n=11只),分別建立動物模型。應(yīng)用腦干誘發(fā)電位儀檢測各組大鼠用藥前后的腦干誘發(fā)電位聽閾(auditory brainstem response, ABR)變化；分別采用基底膜鋪片和血管紋鋪片觀察各組大鼠耳蝸毛細(xì)胞及微循環(huán)的形態(tài)變化情況；應(yīng)用免疫組化SP法觀察各組藥物對耳蝸外側(cè)壁內(nèi)皮素A(ET-A)受體的表達(dá)情況的影響。采用SPSS13.0統(tǒng)計軟件對ABR變化情況的組間比較和各組ET-A的表達(dá)變化比較均采用校正t檢驗進(jìn)行統(tǒng)計分析。 研究結(jié)果：肌注慶大霉素組大鼠ABR聽閾較對照組顯著提高(P0.05)且慶大霉素組的ABR變化顯著高于聯(lián)合用藥組ABR的聽閾變化,差異具有統(tǒng)計學(xué)意義(P＜0.05)；聯(lián)合用藥組ABR變化略高于對照組ABR變化,P0.05,差異無統(tǒng)計學(xué)意義(P＞0.05)。慶大霉素組毛細(xì)胞排列雜亂、出現(xiàn)明顯缺失,血管紋毛細(xì)血管網(wǎng)呈明顯收縮缺血狀態(tài)；聯(lián)合用藥組毛細(xì)胞排列紊亂、散在缺失,血管紋毛細(xì)血管網(wǎng)無明顯收縮缺血改變。ET-A主要分布于血管紋中間細(xì)胞和微血管壁周圍細(xì)胞,對照組與聯(lián)合用藥組呈弱陽性(+),慶大霉素組呈強陽性(+++)。 研究結(jié)論： 1.慶大霉素肌肉注射可顯著提高大鼠的聽閾,引起明顯的聽力下降,阿魏酸鈉可有效拮抗慶大霉素對大鼠的耳毒性作用,保護(hù)大鼠聽力。 2.慶大霉素可引起耳蝸毛細(xì)胞的壞死凋亡及耳蝸外側(cè)壁血管紋毛細(xì)血管網(wǎng)強烈收縮,提示慶大霉素可引起耳蝸外側(cè)壁微循環(huán)障礙,推測耳蝸外側(cè)壁微循環(huán)障礙參與慶大霉素耳毒性作用；阿魏酸鈉與慶大霉素聯(lián)合用藥可有效保護(hù)毛細(xì)胞減輕損傷,改善耳蝸外側(cè)壁微循環(huán)。 3.耳蝸外側(cè)壁ET-A可能參與慶大霉素致耳毒性的過程,阿魏酸鈉可能通過抑制ET-A作用來拮抗慶大霉素的毒副作用。 4.慶大霉素耳毒性引起的耳蝸外側(cè)壁微循環(huán)障礙和ET-A表達(dá)的增加可能為明確氨基糖甙類藥物致耳毒性的機(jī)制提供理論依據(jù),阿魏酸鈉的有效保護(hù)作用可能為臨床氨基糖甙類藥物致耳毒性的預(yù)防治療提供新的治療策略。
[Abstract]:The background and purpose of the study: Gentamicin is a common amino-sugar-type antibiotic in clinical application. The sensorineural hearing loss caused by ototoxicity is more common, but the mechanism of ototoxicity is not clear, and there is no ideal method for prevention at present. In this study, a model of gentamicin-induced deafness was constructed to observe the morphological changes of the hair cells in the basilar membrane of the cochlea during the ototoxicity of the gentamicin, the pathological changes of the capillary network of the external wall of the cochlea and the change of the expression of ET-A. To study the possible mechanism of gentamicin ototoxicity, and to further study the protective effect of sodium ferulate on the ototoxicity of gentamicin, the method of reducing the ototoxicity of gentamicin was sought. Methods:32 Wistar rats were randomly divided into three groups: control group (n = 8), gentamicin group (n = 13,150 mg/ kg muscle injection for 7 days), gentamicin (150 mg/ kg intramuscular injection for 7 days) and sodium ferulate (50 mg/ kg intramuscular injection for 7 days). 1), respectively set up A brain-stem evoked potential (BAEP) was used to detect the changes of the auditory brainstem response (ABR) in the rat's cochlea before and after the treatment. The expression of endothelin A (ET-A) receptor in the outer wall of the cochlea was observed by immunohistochemical SP method. The effect of the statistical software of SPSS13.0 on the change of the ABR and the change of the expression of ET-A in each group were compared with the corrected t-test. The results of the study showed that the ABR threshold in the gentamycin group was significantly higher than that in the control group (P0.05), and the ABR change of the gentamycin group was significantly higher than that of the ABR in the combination group (P <0.05). The ABR of the combined group was slightly higher than that of the control group. The difference was not significant (P <0.05) (P <0.05). P> 0.05). The hair cells of the gentamycin group were arranged in a disorder, the appearance of the hair cells in the vein was obviously absent, and the capillary network of the blood vessel was in the state of ischemia. The arrangement of hair cells in the combination group was disordered, and the capillary network of the vein pattern was not clear. ET-A was mainly distributed in the peripheral cells of the vessel and the peripheral cells of the microvessel wall. The control group and the combination group showed a weak positive (+) and the gentamycin group was strong. Positive (+ + Conclusion:1. The results of the study:1. The intramuscular injection of gentamicin can significantly improve the hearing threshold of the rat, cause a significant decrease in the hearing, and the sodium ferulate can effectively antagonize the gentamicin. 2. Gentamicin can cause the necrosis of the hair cells of the cochlea and the strong contraction of the capillary network of the external wall of the cochlea, suggesting that the gentamicin can cause the microcirculation disturbance of the outside wall of the cochlea, and the cochlea can be presumed. The microcirculatory disturbance of the lateral wall is involved in the ototoxicity of gentamicin; the combination of sodium ferulate and gentamicin can be effectively preserved. 3. The lateral wall ET-A of the cochlea may be involved in the ototoxicity of the gentamicin, and the sodium ferulate may Can antagonize the toxic and side effects of gentamicin by inhibiting the effect of ET-A. It is possible to provide a theoretical basis for the mechanism of the ototoxicity of a clear amino sugar drug, and the effective protection of sodium ferulate may
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2010
【分類號】：R764.35

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相關(guān)期刊論文 前10條

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本文編號：2509043