慢性非细菌性前列腺炎动物模型的建立及脊髓氧化应激参与CP/CPPS疼痛的神经机制研究
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摘要
目的：1.探讨3%λ-角叉菜胶前列腺内注射建立大鼠非细菌性前列腺炎模型的有效性和持续时间；2.探讨脊髓氧化应激与前列腺炎的关系及其可能作用机制；3.探讨N-乙酰半胱氨酸(NAC)治疗模型大鼠前列腺炎的效果及其机制。
方法：选用SD大鼠为实验动物,麻醉无菌条件下向其前列腺左右腹侧叶各注入3%λ-角叉菜胶各50u1建立大鼠非细菌性前列腺炎模型,对照组注入等量生理盐水。分别在24小时、7天、14天、30天时间点测机械痛和热痛阈值,处死后取其前列腺行组织学检查,并以Western-blot法检测前列腺COX-2表达；以Evens blue渗漏测定评估血浆渗漏情况评估前列腺局部炎症。
同法建模,分别在相应时间点处死大鼠取L6-S1段脊髓,以酶联免疫吸附法(ELISA)测定脊髓8-异前列腺素(8-epi PGF2a)含量；以黄嘌呤氧化酶法测定脊髓组织总超氧化物歧化酶(T-SOD)的活力；以caspase-3免疫荧光法检测脊髓神经元凋亡水平。
10%N-乙酰半胱氨酸于建模前半小时及术后一周每日腹腔注射(300mg/kg),角叉菜胶前列腺内注射后24h、7天测机械痛和热痛阈值,处死大鼠取前列腺及L6-S1段脊髓,分别检测前列腺COX2蛋白、脊髓8-异前列腺素、SOD活力、细胞凋亡情况。
结果：3%λ-角叉菜胶SD大鼠前列腺内注射后24小时,前列腺间质内出现明显炎细胞聚集,机械痛和热痛阈值均较对照组显著下降(p=0.022, p=0.014), COX2蛋白表达明显增多(p=0.025), Evens blue渗出量显著增加(p<0.001)；随时间推移,疼痛阈值持续下降,机械痛阈值下降持续约1-2周,2周时恢复正常;热痛阈值下降持续约2-4周,30天时恢复正常;COX2表达量升高持续约2-4周,30天时恢复正常;Evens blue渗出增加持续约2-4周,30天时恢复正常。
随着痛阈下降,脊髓氧化应激程度加剧。与对照组相比,7天时脊髓8-epi PGF2a含量显著上升(p=0.008),SOD活力显著下降(p=0.001),14天时仍有显著差异(p=0.001,p=0.012),30天时均恢复正常。7天、14天时实验组脊髓caspase-3荧光染色强度明显强于对照组,24小时、30天时与对照组无显著差异。
与单纯模型组相比,NAC干预组大鼠热痛和机械痛阈值在角叉菜胶前列腺内注射后24小时、7天显著提升；COX2蛋白表达量下降(P=0.046,P=0.027)；脊髓8-epi PGF2a含量降低,24小时时无统计学意义,7天具有显著差异(P=0.035)；SOD活力升高,但差别无统计学意义；7天时干预组caspase-3荧光染色强度弱于模型组,与对照组相当。
结论：1.3%λ-角叉菜胶前列腺内注射建立大鼠非细菌性前列腺炎模型安全有效,诱导炎症至少持续2周；2.角叉菜胶所诱导大鼠非细菌性前列腺炎模型L6-S1段脊髓中枢存在明显氧化应激。提示脊髓初级中枢病变与非细菌性前列腺炎关系密切；3.脊髓中枢氧化应激可能通过诱导神经元细胞凋亡导致非细菌性前列腺炎疼痛症状的持续和泛化；4.N-乙酰半胱氨酸能够有效改善角叉菜胶诱导的非细菌性前列腺炎动物模型局部炎症及脊髓氧化应激。提示NAC具备临床治疗CP/CPPS的潜力。
Objectives:1. To develop an animal model for nonbacterial chronic prostatitis in rats with the use of intraprostatic injection of3%λ-carrageenan, and to assess the validity and duration of this model;2. To investigate the role of increased oxidative stress and oxidative damage of spinal cord in nonbacterial chronic prostatitis in rats induced by intraprostatic λ-carrageenan injection, and to explore its possible mec-hanism;3. To investigate the effect of N-acetylcysteine(NAC) on nonbacterial chronic prostatitis induced by intraprostatic λ-carrageenan injection in rats and its possible mechanism.
Methods:Male Sprague-Dawley rats weighing250-350g were used for the experiments. In experimental groups(n=40),50ul3%λ-carrageenan was injected into the ventral prostate in SD rats under the condition of anesthesia and sterile.50ul of sterile normal saline was injected into the control group. At different time points(before and after24h,7d,14d and30d of injection), radiant heat and von Frey filaments (mechanical stimuli) were applied to the scrotum of rats. The escape latency (s) from radiantheat, and the bending force (g) of the filament to which the animal responded by moving were taken as measures of heat and mechanical thresholds respectively. After determination of these thresholds, the prostate was removed. The expression of cyclooxygenase-2(COX2) in prostate was determined by Western-blot. Evans blue(50mg/kg) was also injected intravenously to assess for plasma protein extravasation at different time points after injection of λ-carrageenan.50ul3%carrageenan was injected into both right and left ventral lobes of the prostate gland in SD rats(n=20). At different time points(before and after24h,7d,14d and30d of injection), after measures of heat and mechanical thresholds, rats were sacrificed and the L6-S1spinal cord were assayed. The level of8-isoprostane(8-epi PGF2a) and superoxide dismutase(SOD) in spinal cord were examined by enzyme linked immunosorbent assay(ELISA) and xanthine oxidase respectively and caspase-3expression was evaluated by immunohistochemistry.10%NAC(300mg/kg) was intraperitoneal injection before the surgery and once a day after the surgery for seven days. At24h after the injection of carrageenan and one hour after the last NAC injection, the pain thresholds were examined and prostate and L6-S1spinal cord were removed. The expression of cyclooxygenase-2(COX2),8-isoprostane, SOD and caspase-3were assessed by the same methods.
Results:After injection of λ-carrageenan, compared to control group, inflamed animals showed a significant reduction in mechanical threshold (mechanical allodynia)at24h and7d(p=0.022,0.046, respectively), and a significant reduction in heat threshold (thermal hyperalgesia) at24h,7d and14d(p=0.014,0.018,0.002, respectively) in the scrotal skin. Significant increase of inflammatory cell accumulation, COX2expression and Evans blue extravasation were observed at24h,7d and14d after injection. Intensified extent of oxidative stress of spinal cord was found as the pain thresholds decreased. The level of8-isoprostane in L6-S1spinal cord of inflamed animals increased and activity of SOD declined significantly at7d after injection(p=0.008, p=0.001respectively). Significant difference still remained by the14th day but it returned to normal by the30day. L6-S1spinal cord caspase-3fluorescence staining in the experimental group showed much more intensity than control group by the7th and14th day after injection while no substantial difference was found by the24th hour and the30th day. Compared with the simple model group, the heat and mechanical thresholds in NAC intervention group increased significantly by the24th hour and the7th day after intraprostatic injection of3%λ-carrageenan, and COX2expression in prostate was significantly reduced(P=0.046, P=0.027). Level of8-epi PGF2a in spinal cord was decreased with no statistical significance by the24th hour but significant lower(P=0.035) by the7th day. Caspase-3fluorescence staining in intervention group was less intensive than that in model group at7d after injection.
Conclusion:1. It is safe and effective to develop the animal model for nonbacterial chronic prostatitis in rats with the use of intraprostatic injection of3%λ-carrageenan, and its duration is more than2weeks;2. There exist increased oxidative stress and oxidative damage in L6-S1spinal cord of the animal model induced by intraprostatic λ-carrageenan injection, which suggest oxidative stress in spinal cord is closely associated with nonbacterial chronic prostatitis;3. Neurons apoptosis in L6-S1spinal cord caused by ROS may result in the nonbacterial chronic prostatitis pain of this model rats;4. Systemic NAC administration suppresses the inflammatory in prostate and the increased oxidative stress in spinal cord induced by intraprostatic λ-carrageenan injection. NAC may be a promising drug for treatment of CP/CPPS.
方法：选用SD大鼠为实验动物,麻醉无菌条件下向其前列腺左右腹侧叶各注入3%λ-角叉菜胶各50u1建立大鼠非细菌性前列腺炎模型,对照组注入等量生理盐水。分别在24小时、7天、14天、30天时间点测机械痛和热痛阈值,处死后取其前列腺行组织学检查,并以Western-blot法检测前列腺COX-2表达；以Evens blue渗漏测定评估血浆渗漏情况评估前列腺局部炎症。
同法建模,分别在相应时间点处死大鼠取L6-S1段脊髓,以酶联免疫吸附法(ELISA)测定脊髓8-异前列腺素(8-epi PGF2a)含量；以黄嘌呤氧化酶法测定脊髓组织总超氧化物歧化酶(T-SOD)的活力；以caspase-3免疫荧光法检测脊髓神经元凋亡水平。
10%N-乙酰半胱氨酸于建模前半小时及术后一周每日腹腔注射(300mg/kg),角叉菜胶前列腺内注射后24h、7天测机械痛和热痛阈值,处死大鼠取前列腺及L6-S1段脊髓,分别检测前列腺COX2蛋白、脊髓8-异前列腺素、SOD活力、细胞凋亡情况。
结果：3%λ-角叉菜胶SD大鼠前列腺内注射后24小时,前列腺间质内出现明显炎细胞聚集,机械痛和热痛阈值均较对照组显著下降(p=0.022, p=0.014), COX2蛋白表达明显增多(p=0.025), Evens blue渗出量显著增加(p<0.001)；随时间推移,疼痛阈值持续下降,机械痛阈值下降持续约1-2周,2周时恢复正常;热痛阈值下降持续约2-4周,30天时恢复正常;COX2表达量升高持续约2-4周,30天时恢复正常;Evens blue渗出增加持续约2-4周,30天时恢复正常。
随着痛阈下降,脊髓氧化应激程度加剧。与对照组相比,7天时脊髓8-epi PGF2a含量显著上升(p=0.008),SOD活力显著下降(p=0.001),14天时仍有显著差异(p=0.001,p=0.012),30天时均恢复正常。7天、14天时实验组脊髓caspase-3荧光染色强度明显强于对照组,24小时、30天时与对照组无显著差异。
与单纯模型组相比,NAC干预组大鼠热痛和机械痛阈值在角叉菜胶前列腺内注射后24小时、7天显著提升；COX2蛋白表达量下降(P=0.046,P=0.027)；脊髓8-epi PGF2a含量降低,24小时时无统计学意义,7天具有显著差异(P=0.035)；SOD活力升高,但差别无统计学意义；7天时干预组caspase-3荧光染色强度弱于模型组,与对照组相当。
结论：1.3%λ-角叉菜胶前列腺内注射建立大鼠非细菌性前列腺炎模型安全有效,诱导炎症至少持续2周；2.角叉菜胶所诱导大鼠非细菌性前列腺炎模型L6-S1段脊髓中枢存在明显氧化应激。提示脊髓初级中枢病变与非细菌性前列腺炎关系密切；3.脊髓中枢氧化应激可能通过诱导神经元细胞凋亡导致非细菌性前列腺炎疼痛症状的持续和泛化；4.N-乙酰半胱氨酸能够有效改善角叉菜胶诱导的非细菌性前列腺炎动物模型局部炎症及脊髓氧化应激。提示NAC具备临床治疗CP/CPPS的潜力。
Objectives:1. To develop an animal model for nonbacterial chronic prostatitis in rats with the use of intraprostatic injection of3%λ-carrageenan, and to assess the validity and duration of this model;2. To investigate the role of increased oxidative stress and oxidative damage of spinal cord in nonbacterial chronic prostatitis in rats induced by intraprostatic λ-carrageenan injection, and to explore its possible mec-hanism;3. To investigate the effect of N-acetylcysteine(NAC) on nonbacterial chronic prostatitis induced by intraprostatic λ-carrageenan injection in rats and its possible mechanism.
Methods:Male Sprague-Dawley rats weighing250-350g were used for the experiments. In experimental groups(n=40),50ul3%λ-carrageenan was injected into the ventral prostate in SD rats under the condition of anesthesia and sterile.50ul of sterile normal saline was injected into the control group. At different time points(before and after24h,7d,14d and30d of injection), radiant heat and von Frey filaments (mechanical stimuli) were applied to the scrotum of rats. The escape latency (s) from radiantheat, and the bending force (g) of the filament to which the animal responded by moving were taken as measures of heat and mechanical thresholds respectively. After determination of these thresholds, the prostate was removed. The expression of cyclooxygenase-2(COX2) in prostate was determined by Western-blot. Evans blue(50mg/kg) was also injected intravenously to assess for plasma protein extravasation at different time points after injection of λ-carrageenan.50ul3%carrageenan was injected into both right and left ventral lobes of the prostate gland in SD rats(n=20). At different time points(before and after24h,7d,14d and30d of injection), after measures of heat and mechanical thresholds, rats were sacrificed and the L6-S1spinal cord were assayed. The level of8-isoprostane(8-epi PGF2a) and superoxide dismutase(SOD) in spinal cord were examined by enzyme linked immunosorbent assay(ELISA) and xanthine oxidase respectively and caspase-3expression was evaluated by immunohistochemistry.10%NAC(300mg/kg) was intraperitoneal injection before the surgery and once a day after the surgery for seven days. At24h after the injection of carrageenan and one hour after the last NAC injection, the pain thresholds were examined and prostate and L6-S1spinal cord were removed. The expression of cyclooxygenase-2(COX2),8-isoprostane, SOD and caspase-3were assessed by the same methods.
Results:After injection of λ-carrageenan, compared to control group, inflamed animals showed a significant reduction in mechanical threshold (mechanical allodynia)at24h and7d(p=0.022,0.046, respectively), and a significant reduction in heat threshold (thermal hyperalgesia) at24h,7d and14d(p=0.014,0.018,0.002, respectively) in the scrotal skin. Significant increase of inflammatory cell accumulation, COX2expression and Evans blue extravasation were observed at24h,7d and14d after injection. Intensified extent of oxidative stress of spinal cord was found as the pain thresholds decreased. The level of8-isoprostane in L6-S1spinal cord of inflamed animals increased and activity of SOD declined significantly at7d after injection(p=0.008, p=0.001respectively). Significant difference still remained by the14th day but it returned to normal by the30day. L6-S1spinal cord caspase-3fluorescence staining in the experimental group showed much more intensity than control group by the7th and14th day after injection while no substantial difference was found by the24th hour and the30th day. Compared with the simple model group, the heat and mechanical thresholds in NAC intervention group increased significantly by the24th hour and the7th day after intraprostatic injection of3%λ-carrageenan, and COX2expression in prostate was significantly reduced(P=0.046, P=0.027). Level of8-epi PGF2a in spinal cord was decreased with no statistical significance by the24th hour but significant lower(P=0.035) by the7th day. Caspase-3fluorescence staining in intervention group was less intensive than that in model group at7d after injection.
Conclusion:1. It is safe and effective to develop the animal model for nonbacterial chronic prostatitis in rats with the use of intraprostatic injection of3%λ-carrageenan, and its duration is more than2weeks;2. There exist increased oxidative stress and oxidative damage in L6-S1spinal cord of the animal model induced by intraprostatic λ-carrageenan injection, which suggest oxidative stress in spinal cord is closely associated with nonbacterial chronic prostatitis;3. Neurons apoptosis in L6-S1spinal cord caused by ROS may result in the nonbacterial chronic prostatitis pain of this model rats;4. Systemic NAC administration suppresses the inflammatory in prostate and the increased oxidative stress in spinal cord induced by intraprostatic λ-carrageenan injection. NAC may be a promising drug for treatment of CP/CPPS.
引文
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