糖皮质激素和细胞因子与海马突触损害的关系及抗炎细胞因子IL-10的保护作用
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摘要
第一部分慢性给予应激水平的糖皮质激素对海马神经元和突触的影响
为探讨慢性给予应激水平糖皮质激素(glucocorticoid)对大鼠海马的影响，在实验组大鼠饮用水中加入皮质醇，使动物皮质醇吸收量达10mg／kg／day，从而引起与应激动物相同的皮质醇水平，共21天，然后用免疫组织化学和Western blot的方法观察海马Caspase-3、Synaptophysin(Syn)和Neurogranin(Ng)表达的变化。结果显示：①与正常组相比，实验组大鼠海马结构中可见较多的细胞萎缩，海马各CA区和DG区未见或偶见极个别Caspase-3免疫反应阳性细胞，但在下托和压部后皮质中，可见有较多的Caspase-3免疫反应阳性细胞；②与正常组Syn和Ng表达水平(1.2197±0.3443和1.9330±0.3450)相比，实验组大鼠海马结构中Syn和Ng的表达明显减少(P＜0.05)，其表达水平分别为0.5512±0.0540和1.3375±0.3317。上述结果表明，慢性给予应激水平的糖皮质激素可损伤海马的功能，引起不依赖Caspase-3的海马神经细胞退变、使海马突触数量减少以及改变海马突触效能可能是其作用的部分机制。
第二部分胸腺缺陷与海马损害的关系研究
目的：探讨胸腺缺陷与海马损害的关系及其可能作用机制。方法：随机选取10～12周龄、22～24周龄的雄性裸小鼠(Balb／c-nu／nu)各6只作实验组，以同周龄、同数量、同性别的正常Balb／c小鼠作对照组，用ELISA方法检测小鼠血清和海马促炎细胞因子IL-2、IFN-γ、TNF-α的含量和Western blot方法分析海马突触蛋白Synaptophysin(Syn)、Neurogranin(Ng)的表达水平。结果：①10～12周龄实验组小鼠血清促炎细胞因子IFN-γ和TNF-α含量分别为184.98±81.69pg／ml和113.16±6.60pg／ml，显著高于同周龄对照组的71.81±9.76pg／ml(P＜0.05)和91.38±6.14(P＜0.01)；②22～24周龄实验组小鼠海马促炎细胞因子IFN-γ含量(6.97±0.64pg／mg海马组织)显著高于同周龄对照组(5.72±0.31pg／mg海马组织)(P＜0.01)：③22～24周龄实验组小鼠海马Syn表达水平显著低于同周龄对照组(对照组为0.7044±0.0882，实验组为0.5513±0.1096，P＜0.05)，并伴有Ng表达水平的升高(对照组为1.3030±0.2607，实验组为1.7484±0.2191，P＜0.01)。结论：胸腺缺陷会导致海马功能的损害，其机制可能与其所致的促炎细胞因子水平增高有关。
第三部分抗炎细胞因子IL-10对糖皮质激素所致海马突触损害的保护作用
目的探讨GC是否可通过引起促炎细胞因子作用增强来损害海马，以及抗炎细胞因子IL-10对GC所致海马损害的保护作用。方法①在原代培养的海马细胞中给予皮质醇8×10~(-6)mol／L，12h后用RT-PCR的方法观察其对海马细胞促炎细胞因子IFN-γ表达的影响；②构建IL-10真核表达质粒，并将其通过侧脑室插管注射到正通过饮水给予皮质醇(40mg/L，共21d)的Wistar大鼠脑中(80ng/20μl，每间隔4d注射1次，即在第1，5，9，13和17天注射)，然后用Western blot的方法观察其对海马突触蛋白Synapsin I和Neurogranin(Ng)表达的影响。结果①皮质醇可引起原代培养的海马细胞促炎细胞因子IFN-γmRNA表达增加：皮质醇组IFN-γmRNA表达水平为0.5940+0.0448(n=4)，对照组为0.4237+0.0915(n=4)，p＜0.05；②侧脑室给予IL-10的实验组大鼠Synapsin I和Ng的表达水平分别为2.0171±0.2527、1.9653+0.0843(n=7)，显著高于对照组的1.1440±0.2152、1.5344±0.1763(n=7)，p＜0.01。结论促炎细胞因子可能参与了糖皮质激素对海马的损害，IL-10对糖皮质激素所致的海马损害有保护作用。
Effects of chronic stressed level of glucocorticoid treatment on neurons and synapses in hippocampus
To explore the effect of chronic stressesd level of glucocorticoid
on hippocampus, the rats in treatment group were provided with hydrocortisone (cortisol) 10mg/kg/day in drinking water for 21 days. Then the expressions of Caspase-3, Synaptophysin (Syn) and Neurogranin (Ng) in hippocampus of two groups were observed by immunohistochemistry staining and assayed by Western blot. The results are as follows: ① In the treatment group, many neuronal atrophy was seen in hippocampus, and Caspase-3 immunoreactive positive cells were not seen or just were seen occasionally in CA regions and dentate gyrus, but many Caspase-3 immunoreactive positive cells were seen in subiculum and retrosplenial cortex; ②The results of Western blot showed the expression levels of Syn (0.5512±0.0540) and Ng (1.3375±0.3317) in the treatment group were significantly lower than those of the control group (P<0.05), which were 1.2197±0.3443 and 1.9330±0.3450, respectively. The results indicated that administration with chronic stressesd level of glucocorticoid may damage the functions of hippocampus by resulting in caspase-3-independent degeneration of neurons in hippocampus and changes in synapse efficacy and number in hippocampus. Study on the relationship between deficit in thymus and impaired hippocampus
objective: To explore the effects of deficit in thymus on the hippocampus. Methods: Six 10～12 weeks and six 22～24 weeks of age of male nude mice (Balb/c-nu/nu mice) and the same age and the same number of male healthy mice (normal Balb/c mice) were randomly selected as experimental groups or control groups. Then the contents of proinflammatory cytokines IL-2, IFN-γ and TNF-α in serum and the hippocampus of both groups were measured by ELISA method and the expression levels of Synaptophysin (Syn) and Neurogranin (Ng) in the hippocampus of both groups were analyzed by Western blot method. Results: ① The contents of proinflammatory cytokine IFN-γ (184.98±81.69pg/ml) and TNF-α(113.16±6.60pg/ml) of serum in experimental group of 10～12 weeks of age were higher significantly than those in control group of the same age, which were 71.81±9.76pg/ml (P<0.05) and 91.38±6.14 pg/ml (P<0.01), respectively. (2) The contents of proinflammatory cytokine IFN-γ of the hippocampus in experimental group of 22～24 weeks of age (6.97±0.64pg/mg hippocampus, wet weight) was higher significantly than that in control group of the same age (5.72±0.31pg/mg hippocampus, wet weight, P<0.01); ③ the expression level of Syn was lower significantly in experimental group of 22～24 weeks of age (0.5513±0.1096) than that in control group of the same age (0.7044±0.0882, P<0.05), while the expression level of Ng was higher significantly in experimental group of 22～24 weeks of age (1.7484±0.2191) than that in control group of the same age (1.3030±0.2607, P<0.01). Conclusion: Deficit in thymus may affect the functions of the hippocampus adversely by increasing the contents of proinflammatory cytokines. IL-10 may prevent damage of synapse in hippocampus caused by glucocorticoid
Objective: to investigate whether IL-10 may prevent damage of synapse in the hippocampus caused by glucocoticoids (GCs), and reveal the potential mechanism of GCs effect adversely on the hippocampus by enhancing pro-inflammatory cytokines. Methods: ①Primary hippocampal neurons cultured were divided into control group and group treated with cortisol 8×10~(-6) mol/L, and then the expression levels of IFN-γ mRNA of both groups were analyzed by RT-PCR method. ②After pIRES-hrGFP-2a -IL-10 eukaryotic expression Plasmid was constructed, the plasmid was injected into the right lateral ventricle of each rat (80ng in 20μl) by intracerebroventricular cannuia five times at 4-day intervals (i.e., on day 1, 5, 9, 13 and 17) while the rats were administered with cortisol dissolved in drinking water (40mg/L) at the same time for 21 days (i.e., from day 1 to 21). For the control group, empty vector instead of the expression plasmid pIRES-hrGFP-2a-IL-10 was injected to the same place. Then the expression levels of Synapsin I and Neurogranin (Ng) in the hippocampus of both groups were assayed by Western blot method. Results: ① IFN-γ mRNA expression level of primary hippocampal cell cultures in the experimental group treated with cortisol (0.5940±0.0448, n=4) was significantly higher than that in the control group (0.4237±0.0915, n=4), p <0.05; (2) The expression levels of Synapsin I protein (2.0171±0.2527) and Neurogranin protein (1.9653 ±0.0843) in the experimental group (n=7) treated with plasmid pIRES -hrGFP-2a-IL-10 were markedly higher than those in the control group treated with empty plasmid pIRES-hrGFP-2a, which were 1.1440±0.2152 and 1.5344±0.1763, respectively (n=7), p<0.01. Conclusion: GCs may effect adversely on the hippocampus by enhancing pro-inflammatory cytokines, and anti-inflammatory cytokine IL-10 may prevent damage of synapse in the hippocampus caused by GCs.
为探讨慢性给予应激水平糖皮质激素(glucocorticoid)对大鼠海马的影响，在实验组大鼠饮用水中加入皮质醇，使动物皮质醇吸收量达10mg／kg／day，从而引起与应激动物相同的皮质醇水平，共21天，然后用免疫组织化学和Western blot的方法观察海马Caspase-3、Synaptophysin(Syn)和Neurogranin(Ng)表达的变化。结果显示：①与正常组相比，实验组大鼠海马结构中可见较多的细胞萎缩，海马各CA区和DG区未见或偶见极个别Caspase-3免疫反应阳性细胞，但在下托和压部后皮质中，可见有较多的Caspase-3免疫反应阳性细胞；②与正常组Syn和Ng表达水平(1.2197±0.3443和1.9330±0.3450)相比，实验组大鼠海马结构中Syn和Ng的表达明显减少(P＜0.05)，其表达水平分别为0.5512±0.0540和1.3375±0.3317。上述结果表明，慢性给予应激水平的糖皮质激素可损伤海马的功能，引起不依赖Caspase-3的海马神经细胞退变、使海马突触数量减少以及改变海马突触效能可能是其作用的部分机制。
第二部分胸腺缺陷与海马损害的关系研究
目的：探讨胸腺缺陷与海马损害的关系及其可能作用机制。方法：随机选取10～12周龄、22～24周龄的雄性裸小鼠(Balb／c-nu／nu)各6只作实验组，以同周龄、同数量、同性别的正常Balb／c小鼠作对照组，用ELISA方法检测小鼠血清和海马促炎细胞因子IL-2、IFN-γ、TNF-α的含量和Western blot方法分析海马突触蛋白Synaptophysin(Syn)、Neurogranin(Ng)的表达水平。结果：①10～12周龄实验组小鼠血清促炎细胞因子IFN-γ和TNF-α含量分别为184.98±81.69pg／ml和113.16±6.60pg／ml，显著高于同周龄对照组的71.81±9.76pg／ml(P＜0.05)和91.38±6.14(P＜0.01)；②22～24周龄实验组小鼠海马促炎细胞因子IFN-γ含量(6.97±0.64pg／mg海马组织)显著高于同周龄对照组(5.72±0.31pg／mg海马组织)(P＜0.01)：③22～24周龄实验组小鼠海马Syn表达水平显著低于同周龄对照组(对照组为0.7044±0.0882，实验组为0.5513±0.1096，P＜0.05)，并伴有Ng表达水平的升高(对照组为1.3030±0.2607，实验组为1.7484±0.2191，P＜0.01)。结论：胸腺缺陷会导致海马功能的损害，其机制可能与其所致的促炎细胞因子水平增高有关。
第三部分抗炎细胞因子IL-10对糖皮质激素所致海马突触损害的保护作用
目的探讨GC是否可通过引起促炎细胞因子作用增强来损害海马，以及抗炎细胞因子IL-10对GC所致海马损害的保护作用。方法①在原代培养的海马细胞中给予皮质醇8×10~(-6)mol／L，12h后用RT-PCR的方法观察其对海马细胞促炎细胞因子IFN-γ表达的影响；②构建IL-10真核表达质粒，并将其通过侧脑室插管注射到正通过饮水给予皮质醇(40mg/L，共21d)的Wistar大鼠脑中(80ng/20μl，每间隔4d注射1次，即在第1，5，9，13和17天注射)，然后用Western blot的方法观察其对海马突触蛋白Synapsin I和Neurogranin(Ng)表达的影响。结果①皮质醇可引起原代培养的海马细胞促炎细胞因子IFN-γmRNA表达增加：皮质醇组IFN-γmRNA表达水平为0.5940+0.0448(n=4)，对照组为0.4237+0.0915(n=4)，p＜0.05；②侧脑室给予IL-10的实验组大鼠Synapsin I和Ng的表达水平分别为2.0171±0.2527、1.9653+0.0843(n=7)，显著高于对照组的1.1440±0.2152、1.5344±0.1763(n=7)，p＜0.01。结论促炎细胞因子可能参与了糖皮质激素对海马的损害，IL-10对糖皮质激素所致的海马损害有保护作用。
Effects of chronic stressed level of glucocorticoid treatment on neurons and synapses in hippocampus
To explore the effect of chronic stressesd level of glucocorticoid
on hippocampus, the rats in treatment group were provided with hydrocortisone (cortisol) 10mg/kg/day in drinking water for 21 days. Then the expressions of Caspase-3, Synaptophysin (Syn) and Neurogranin (Ng) in hippocampus of two groups were observed by immunohistochemistry staining and assayed by Western blot. The results are as follows: ① In the treatment group, many neuronal atrophy was seen in hippocampus, and Caspase-3 immunoreactive positive cells were not seen or just were seen occasionally in CA regions and dentate gyrus, but many Caspase-3 immunoreactive positive cells were seen in subiculum and retrosplenial cortex; ②The results of Western blot showed the expression levels of Syn (0.5512±0.0540) and Ng (1.3375±0.3317) in the treatment group were significantly lower than those of the control group (P<0.05), which were 1.2197±0.3443 and 1.9330±0.3450, respectively. The results indicated that administration with chronic stressesd level of glucocorticoid may damage the functions of hippocampus by resulting in caspase-3-independent degeneration of neurons in hippocampus and changes in synapse efficacy and number in hippocampus. Study on the relationship between deficit in thymus and impaired hippocampus
objective: To explore the effects of deficit in thymus on the hippocampus. Methods: Six 10～12 weeks and six 22～24 weeks of age of male nude mice (Balb/c-nu/nu mice) and the same age and the same number of male healthy mice (normal Balb/c mice) were randomly selected as experimental groups or control groups. Then the contents of proinflammatory cytokines IL-2, IFN-γ and TNF-α in serum and the hippocampus of both groups were measured by ELISA method and the expression levels of Synaptophysin (Syn) and Neurogranin (Ng) in the hippocampus of both groups were analyzed by Western blot method. Results: ① The contents of proinflammatory cytokine IFN-γ (184.98±81.69pg/ml) and TNF-α(113.16±6.60pg/ml) of serum in experimental group of 10～12 weeks of age were higher significantly than those in control group of the same age, which were 71.81±9.76pg/ml (P<0.05) and 91.38±6.14 pg/ml (P<0.01), respectively. (2) The contents of proinflammatory cytokine IFN-γ of the hippocampus in experimental group of 22～24 weeks of age (6.97±0.64pg/mg hippocampus, wet weight) was higher significantly than that in control group of the same age (5.72±0.31pg/mg hippocampus, wet weight, P<0.01); ③ the expression level of Syn was lower significantly in experimental group of 22～24 weeks of age (0.5513±0.1096) than that in control group of the same age (0.7044±0.0882, P<0.05), while the expression level of Ng was higher significantly in experimental group of 22～24 weeks of age (1.7484±0.2191) than that in control group of the same age (1.3030±0.2607, P<0.01). Conclusion: Deficit in thymus may affect the functions of the hippocampus adversely by increasing the contents of proinflammatory cytokines. IL-10 may prevent damage of synapse in hippocampus caused by glucocorticoid
Objective: to investigate whether IL-10 may prevent damage of synapse in the hippocampus caused by glucocoticoids (GCs), and reveal the potential mechanism of GCs effect adversely on the hippocampus by enhancing pro-inflammatory cytokines. Methods: ①Primary hippocampal neurons cultured were divided into control group and group treated with cortisol 8×10~(-6) mol/L, and then the expression levels of IFN-γ mRNA of both groups were analyzed by RT-PCR method. ②After pIRES-hrGFP-2a -IL-10 eukaryotic expression Plasmid was constructed, the plasmid was injected into the right lateral ventricle of each rat (80ng in 20μl) by intracerebroventricular cannuia five times at 4-day intervals (i.e., on day 1, 5, 9, 13 and 17) while the rats were administered with cortisol dissolved in drinking water (40mg/L) at the same time for 21 days (i.e., from day 1 to 21). For the control group, empty vector instead of the expression plasmid pIRES-hrGFP-2a-IL-10 was injected to the same place. Then the expression levels of Synapsin I and Neurogranin (Ng) in the hippocampus of both groups were assayed by Western blot method. Results: ① IFN-γ mRNA expression level of primary hippocampal cell cultures in the experimental group treated with cortisol (0.5940±0.0448, n=4) was significantly higher than that in the control group (0.4237±0.0915, n=4), p <0.05; (2) The expression levels of Synapsin I protein (2.0171±0.2527) and Neurogranin protein (1.9653 ±0.0843) in the experimental group (n=7) treated with plasmid pIRES -hrGFP-2a-IL-10 were markedly higher than those in the control group treated with empty plasmid pIRES-hrGFP-2a, which were 1.1440±0.2152 and 1.5344±0.1763, respectively (n=7), p<0.01. Conclusion: GCs may effect adversely on the hippocampus by enhancing pro-inflammatory cytokines, and anti-inflammatory cytokine IL-10 may prevent damage of synapse in the hippocampus caused by GCs.
引文
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