發(fā)布時間：2018-06-01 02:27

  本文選題：咪康唑 + OPIDN　； 參考：《河北大學》2017年碩士論文

【摘要】：一些有機磷化合物(organophosphorus compound,OP)能夠引發(fā)一種遲發(fā)性的神經(jīng)病癥,稱為有機磷引起的遲發(fā)性神經(jīng)病(organophosphate-induced delayed neuropathy,OPIDN)。雖然OPIDN事件報道以來已經(jīng)過了一個多世紀,但是其作用機理仍然不清楚,更沒有有效的治療方法。本研究旨在研究咪康唑對OPIDN的影響及作用機理。我們以研究OPIDN常用的成年雞為研究對象,用有機磷化合物磷酸三鄰甲苯酯(tri-ocresyl phosphate,TOCP)為誘導劑,從癥狀得分、組織病理變化和維持髓鞘相關的信號蛋白等多方面探索咪康唑對OPIDN的影響及相關機理。首先將成年雞分為三組(對照組;TOCP組;TOCP+咪康唑組),對照組口服空膠囊,TOCP組和TOCP+咪康唑組給予TOCP(750 mg/kg,po)處理,TOCP+咪康唑組從TOCP染毒第7天開始直到第21天連續(xù)腹腔注射咪康唑(3.5 mg/kg/days)。觀察TOCP單獨處理組發(fā)現(xiàn)從第8天開始成年雞出現(xiàn)輕微的共濟失調,隨著時間的推移毒性癥狀加重(從中度而明顯的不協(xié)調到嚴重性、經(jīng)常性的站立困難),到最后完全癱瘓,根據(jù)癥狀觀察可以得出OPIDN模型誘導成功。與TOCP單獨處理相比,TOCP處理后再給予咪康唑能夠明顯改善TOCP引起的體重降低和毒性癥狀;對脊髓運動神經(jīng)元尼氏體檢測發(fā)現(xiàn),與對照組相比,TOCP單獨處理組尼氏體降低約40%,與TOCP單獨處理組相比,TOCP+咪康唑組恢復到接近對照水平;對坐骨神經(jīng)髓鞘特異性蛋白S100β進行免疫熒光染色,與對照組相比,TOCP單獨處理組引起坐骨神經(jīng)S100β明顯減少,與TOCP單獨處理組相比,TOCP+咪康唑組恢復到接近對照水平;超薄切片觀察脊髓和坐骨神經(jīng)髓鞘的完整性發(fā)現(xiàn),與對照組相比較,TOCP單獨處理組坐骨神經(jīng)髓鞘損傷明顯,而咪康唑能夠明顯改善TOCP引起的這種損傷。為了進一步探索咪康唑如何改善OPIDN,已知ErbB3/Akt和JNK/c-Jun和p38對于維持髓鞘的穩(wěn)定至關重要。因此,我們運用蛋白免疫印跡的方法檢測坐骨神經(jīng)和脊髓組織ErbB3/Akt、JNK/c-Jun和p38以及維持髓鞘穩(wěn)定的結構蛋白P0和MBP的變化。結果表明,與對照組相比,單獨給予TOCP處理引起脊髓和坐骨神經(jīng)ErbB3/Akt信號通路激活,脊髓組織JNK激活而坐骨神經(jīng)JNK抑制,并引起髓磷脂堿性蛋白(myelin basic protein,MBP)的明顯下降。咪康唑可以抑制TOCP引起的ErbB3/Akt信號通路激活,能夠恢復TOCP引起的脊髓組織JNK激活和坐骨神經(jīng)JNK抑制,并且能恢復MBP表達水平。我們以sNF96.2雪旺氏細胞為模型進一步探討咪康唑緩解TOCP引起的遲發(fā)性神經(jīng)毒性作用機理,實驗分為四組:DMSO溶劑對照組;咪康唑單獨處理組;TOCP單獨處理組;TOCP+咪康唑組。用免疫印跡的方法檢測各個處理組ErbB3/Akt信號通路以及MBP的變化,結果顯示,與對照組相比,單獨給予TOCP處理引起雪旺氏細胞ErbB3/Akt信號通路激活以及MBP表達量明顯下降,TOCP與咪康唑共同處理可以抑制TOCP引起的ErbB3/Akt信號通路激活,且能夠恢復MBP表達水平。綜上所述,可以得出咪康唑顯著改善了由TOCP引起的成年雞脊髓和坐骨神經(jīng)的毒性癥狀和組織病理損傷。咪康唑可能通過調控ErbB3/Akt信號通路和JNK表達量來改善OPIDN。
[Abstract]:Some organophosphorus compounds (organophosphorus compound, OP) can cause a delayed neuropathy, known as the organophosphate-induced delayed neuropathy (OPIDN) caused by organophosphorus (OPIDN). Although the OPIDN event has been reported for more than a century, its mechanism is still unclear and less effective. The purpose of this study was to study the effect and mechanism of miconazole on OPIDN. We studied the adult chicken in OPIDN, using organophosphorus phosphate three o toluene (tri-ocresyl phosphate, TOCP) as an inducer, from the symptom score, the tissue disease change and the maintenance of the myelin related signal protein. To explore the effect of miconazole on OPIDN and the related mechanism. First, the adult chickens were divided into three groups (control group, TOCP group, TOCP+ miconazole group), the control group was taken orally empty capsules, the TOCP group and TOCP+ miconazole group were treated with TOCP (750 mg/kg, PO), and the miconazole group began to intraperitoneally injected with midazolazole (3.5 mg/kg/days) from TOCP for seventh days from TOCP. A single treatment group of TOCP found a slight ataxia in the adult chicken from eighth days, and with the passage of time the toxic symptoms increased (from moderate to severe incongruity to severity, frequent standing difficulties), to the final complete paralysis, and the OPIDN model could be induced to be successful according to the symptom observation. Compared with TOCP alone, TOC When treated with P, imidazole could significantly improve the weight loss and toxic symptoms caused by TOCP. The Nissl body detection of spinal motor neurons found that, compared with the control group, the Nissl body decreased by about 40% in the TOCP alone group. Compared with the TOCP alone group, the TOCP+ miconazole group recovered to the control level, and the myelin sheath specificity of the sciatic nerve was specific. Protein S100 beta was stained with immunofluorescence. Compared with the control group, the S100 beta of the sciatic nerve decreased significantly in the TOCP alone group. Compared with the TOCP alone group, the TOCP+ miconazole group recovered to the control level, and the ultrathin section observed the integrity of the myelin myelin sheath and the sciatic nerve. Compared with the control group, TOCP alone treated the sciatic group. In order to further explore how miconazole improves the OPIDN, the known ErbB3/Akt and JNK/c-Jun and p38 are essential for maintaining the stability of the myelin sheath. Therefore, we use the method of protein immunoblotting to detect the ErbB3/Akt in the sciatic and spinal cord tissue, JNK/c-Ju, JNK/c-Ju, JNK/c-Ju, JNK/c-Ju, and p38. The changes in N and p38 and the maintenance of myelin stable structural protein P0 and MBP showed that, compared with the control group, the ErbB3/Akt signaling pathway of the spinal cord and sciatic nerve was activated by TOCP treatment alone, the JNK activation of the spinal cord and the inhibition of the JNK of the sciatic nerve, and the obvious decrease of the myelin alkaline egg white (myelin basic protein, MBP). Azole can inhibit the activation of the ErbB3/Akt signaling pathway induced by TOCP, restore the JNK activation of the spinal cord and the JNK inhibition of the sciatic nerve caused by TOCP, and restore the MBP expression level. We use sNF96.2 Schwann's cell as a model to further explore the mechanism of delayed neurotoxicity induced by miconazole in TOCP, and the experiment is divided into four groups: DMSO The solvent control group, miconazole alone treatment group, TOCP alone treatment group and TOCP+ miconazole group. The changes of ErbB3/Akt signaling pathway and MBP in each treatment group were detected by immunoblotting. The results showed that the ErbB3/Akt signaling pathway activation in Schwann cells and the MBP expression decreased significantly by TOCP treatment compared with the control group, TO. CP combined with miconazole can inhibit the activation of the ErbB3/Akt signaling pathway induced by TOCP and can restore the level of MBP expression. In summary, miconazole can significantly improve the toxic symptoms and histopathological damage of the spinal cord and sciatic nerve of adult chickens caused by TOCP. Miconazole may regulate the ErbB3/Akt signaling pathway and the JNK table. Amount to improve OPIDN.
【學位授予單位】：河北大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R747.9

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