外源性硫化氢对大鼠脑缺血—再灌注损伤的保护作用及机制探讨
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摘要
第一部分不同浓度外源性硫化氢对大鼠脑缺血再灌注损伤的影响
目的：探讨不同浓度外源性硫化氢对脑缺血再灌注大鼠神经功能的作用及其机制。
方法：将288只雄性SD大鼠通过随机数字表法分为4组：假手术组,模型组,小剂量NaHS(3.2mg/kg)组,大剂量NaHS(6.4mg/kg)组,每组72只；线栓法制备大鼠大脑中动脉栓塞模型,2h后再灌注,灌注前20min给予生理盐水或NaHS腹腔注射,术后6h、24h、48h、7d分别行神经功能缺损评分。四氮唑红染色观察脑梗死体积、免疫组化和免疫印迹检测缺血周边区肿瘤坏死因子-α (TNF-α)与热休克蛋白20(HSP20)表达。
结果
①模型组各时刻点均有明显的神经功能缺损症状,随着再灌注时间的延长,神经功能缺损症状逐渐减轻。右侧大脑中动脉供血区可见大小不一苍白色梗死脑组织,NaHS干预后神经功能缺损改善(P<0.05),脑梗死体积减少(P<0.05),以大剂量NaHS组改善效果更明显(P<0.05)。
②免疫组化显示在缺血再灌注后6h～7d,与假手术组相比,缺血周边区模型组TNF-α阳性细胞数增加,分别为17.2±3.2、29.5±3.1、16.1±3.5、4.3±1.5,NaHS干预后TNF-α阳性细胞数减少；小剂量组分别为15.1±2.9、26.2±2.7、15.8土4.1、4.5±1.1(P<0.05),大剂量组减少更明显,分别为13.3士2.6、20.1±2.0、12.2±2.7、4.2±0.6(P<0.05),模型组和干预组比较差异有统计学意义(P<0.05),大剂量组和小剂量组比较差异有统计学意义(P<0.05)。同期与假手术组相比,缺血周边区模型组HSP20阳性细胞数增加,分别为30.2±5.2、52.6±7.0、70.2±7.3、40.2±3.9,NaHS干预后HSP20阳性细胞数较模型组增加,小剂量组分别为40.2±3.7、61.1±7.3、75.4±4.0、40.5±2.1,大剂量组增加更明显,分别为45.3±5.6、67.6±5.1、81.8士6.5、49.6±4.8(P<0.05)。
③免疫印迹检测缺血周边区缺血再灌注各个时刻点TNF-α表达显示,与假手术组相比,模型组各时刻点(7d组除外)TNF-α表达增加,分别为0.74±0.13、1.13±0.19、0.87±0.26(均P<0.05)、0.19±0.03(P>0.05),干预组脑各时刻点较模型组表达均降低,小剂量组为0.32±0.19、0.61±0.14、0.40±0.12、0.23±0.03(均P<0.05),大剂量组更降低,为0.31±0.16、0.444±0.18、0.26±0.13、0.19±0.05(均P<0.05),模型组和干预组相比差异有统计学意义(P<0.05),大剂量组和小剂量组相比差异有统计学意义(P<0.05)。同期与假手术组相比,模型组HSP20表达增加,分别为3.51±0.72、5.13±0.41、7.52±1.31、3.48±0.87(均P<0.05),应用NaHS干预后HSP20表达较模型组增加,小剂量组为4.31±0.91、7.47±0.29、9.144±1.22、3.45±1.07(P<0.05),大剂量组为4.41±0.61、7.56±0.35、10.3±1.03、3.92±1.09(均P<0.05),上述改变以大剂量NaHS组更明显(P<0.05)。
结论：NaHS可能通过抑制TNF-α表达,诱导HSP20表达上调,减少脑梗死体积,从而起到神经保护作用,改善神经功能缺损评分,此作用与剂量相关。图12幅,表5个,参考文献23篇。
第二部分外源性硫化氢对大鼠局灶性脑缺血再灌注损伤的保护机制探讨
目的：通过MAPKs通路探讨外源性硫化氢对局灶性脑缺血再灌注损伤大鼠的神经保护作用机制。
方法：将360只雄性SD大鼠随机分为3组：假手术组,模型组,NaHS (6.4mg/kg)干预组,每组120只,线栓法制备大鼠大脑中动脉栓塞模型,2小时后再灌注,灌注前20分钟给予生理盐水或NaHS腹腔注射,术后6h、24h、48h、3d、7d后行神经功能评分,TTC染色观察脑梗死体积,RT-PCR检测ERK1/2mRNA、P38mRNA和Nrf2mRNA表达,免疫组化与免疫荧光检测p-P38和Nrf2表达,免疫印迹检测海马p-ERK1/2、t-ERK1/2、p-P38、t-P38和Nrf2蛋白表达。
结果：NaHS干预组脑梗死体积和神经功能缺损评分相对于模型组显著减少(P<0.05)；各时刻点ERK1/2mRNA、P38mRNA和Nrf2mRNA的表达干预组较模型组升高(P<0.05)；各时刻点ERK1/2和P38蛋白磷酸化、Nrf2蛋白表达干预组较模型组均升高(P<0.05)。
结论：大鼠脑缺血再灌注损伤后NaHS可能通过诱导ERK1/2和P38蛋白磷酸化,激活下游Nrf2蛋白表达,起到抗氧化应激作用,从而减少脑梗死体积,发挥神经保护作用,改善神经功能缺损。图32幅,表12个,参考文献33篇
Part Ⅰ Neuroprotective mechanism of different concentration of hydrogen sulfide on cerebral ischemia-reperfusion injury in rats
Objective:To investigate the neuro-protective mechanism of exogenous hydrogen sulfide on cerebral ischemia-reperfusion (I/R) in rats.
Methods:A total of288male Sprague-Dawley rats were randomly divided into4groups (n=72),including a sham-operation group (group Ⅰ),an I/R model group (group Ⅱ),a low dose NaHS group (group Ⅲ) and a high dose NaHS group (group Ⅳ). Reversible middle cerebral artery occlusion(MCAO) model was established by intraluminal suture method. However, the rats in sham-operation group were operated on without blockage of the middle cerebral artery. The occlusions in other groups were removed after2h, and20min before the removal of the occlusion,NS,3.2mg/kg NaHS, and6.4mg/kg NaHS were injected into the abdomens of rats in group Ⅱ, Ⅲ, and Ⅳ, respectively. At6h,24h,48h,and7d after the reperfusion,behavioral test was used to evaluate the neurological deficiency, and TTC staining was used to observe volume of cerebral infarction. In addition, the protein expression of heat shock protein20(HSP20) and tumor necrosis factor-alpha(TNF-α) in ischemic cortex were measured by immuno-histochemical method and Western blot.
Results:Compared with I/R group, the neurological deficiency scores and volume of cerebral infarction of the group Ⅲ and Ⅳ were significantly decreased. Furthermore, the protein expression of HSP20in the group Ⅲ, and IV were markedly up-regulated while TNF-a markedly down regulated after the reperfusion.
Conclusion:NaHS may exert anti-necrotic and anti-inflammatory function by inducing the expression of HSP20, inhibiting the expression of TNF-a, and reducing the size of cerebral infarction, and therefore, protecting the neuron after I/R injury.
Part Ⅱ Neuroprotective mechanism of hydrogen sulfide on rats after cerebral ischemia-reperfusion by MAPKs pathway
Objective:To investigate the neuroprotective mechanism of exogenous hydrogen sulfide on rats after cerebral ischemia-reperfusion by MAPKs pathway.
Methods:A total of360Sprague-Dawley male rats were randomly divided into three groups (n=90), including a sham-operation group, an ischemia-reperfusion(I/R) model group, NaHS (6.4mg/kg) group. Reversible middle cerebral artery occlusion(MCAO) model was established by intraluminal suture technique. The rats of sham-operation group were operated on while the middle cerebral artery was not blocked. At6h,24h,48h,3d and7d after the reperfusion, TTC staining was used to observe volume of cerebral infarction. The gene expression of ERK1/2、 P38and Nrf2in the hippocampus was measured by RT-PCR,while the protein expression of p-ERK1/2、t-ERK1/2、p-P38、t-P38and Nrf2was measured by Western blot or immunohistochemical method.
Results:Compared with the I/R group, the volume of cerebral infarction and apoptosis of neurons of NaHS group was significantly lower. The Nrf2protein expression and phosphorylation of ERK1/2and P38in NaHS group increased significantly.
Conclusion:Our animal data suggested that the Nrf2protein expression and the phosphorylation of ERK1/2and P38in the rat ischemic/reperfusion injury brain were decreased strongly after MCAO, NaHS supplement induced and increased significantly relieve the focal cerebral I/R injury, which has anti-oxidative stress effect on the cerebral ischemia-reperfusion injury.
目的：探讨不同浓度外源性硫化氢对脑缺血再灌注大鼠神经功能的作用及其机制。
方法：将288只雄性SD大鼠通过随机数字表法分为4组：假手术组,模型组,小剂量NaHS(3.2mg/kg)组,大剂量NaHS(6.4mg/kg)组,每组72只；线栓法制备大鼠大脑中动脉栓塞模型,2h后再灌注,灌注前20min给予生理盐水或NaHS腹腔注射,术后6h、24h、48h、7d分别行神经功能缺损评分。四氮唑红染色观察脑梗死体积、免疫组化和免疫印迹检测缺血周边区肿瘤坏死因子-α (TNF-α)与热休克蛋白20(HSP20)表达。
结果
①模型组各时刻点均有明显的神经功能缺损症状,随着再灌注时间的延长,神经功能缺损症状逐渐减轻。右侧大脑中动脉供血区可见大小不一苍白色梗死脑组织,NaHS干预后神经功能缺损改善(P<0.05),脑梗死体积减少(P<0.05),以大剂量NaHS组改善效果更明显(P<0.05)。
②免疫组化显示在缺血再灌注后6h～7d,与假手术组相比,缺血周边区模型组TNF-α阳性细胞数增加,分别为17.2±3.2、29.5±3.1、16.1±3.5、4.3±1.5,NaHS干预后TNF-α阳性细胞数减少；小剂量组分别为15.1±2.9、26.2±2.7、15.8土4.1、4.5±1.1(P<0.05),大剂量组减少更明显,分别为13.3士2.6、20.1±2.0、12.2±2.7、4.2±0.6(P<0.05),模型组和干预组比较差异有统计学意义(P<0.05),大剂量组和小剂量组比较差异有统计学意义(P<0.05)。同期与假手术组相比,缺血周边区模型组HSP20阳性细胞数增加,分别为30.2±5.2、52.6±7.0、70.2±7.3、40.2±3.9,NaHS干预后HSP20阳性细胞数较模型组增加,小剂量组分别为40.2±3.7、61.1±7.3、75.4±4.0、40.5±2.1,大剂量组增加更明显,分别为45.3±5.6、67.6±5.1、81.8士6.5、49.6±4.8(P<0.05)。
③免疫印迹检测缺血周边区缺血再灌注各个时刻点TNF-α表达显示,与假手术组相比,模型组各时刻点(7d组除外)TNF-α表达增加,分别为0.74±0.13、1.13±0.19、0.87±0.26(均P<0.05)、0.19±0.03(P>0.05),干预组脑各时刻点较模型组表达均降低,小剂量组为0.32±0.19、0.61±0.14、0.40±0.12、0.23±0.03(均P<0.05),大剂量组更降低,为0.31±0.16、0.444±0.18、0.26±0.13、0.19±0.05(均P<0.05),模型组和干预组相比差异有统计学意义(P<0.05),大剂量组和小剂量组相比差异有统计学意义(P<0.05)。同期与假手术组相比,模型组HSP20表达增加,分别为3.51±0.72、5.13±0.41、7.52±1.31、3.48±0.87(均P<0.05),应用NaHS干预后HSP20表达较模型组增加,小剂量组为4.31±0.91、7.47±0.29、9.144±1.22、3.45±1.07(P<0.05),大剂量组为4.41±0.61、7.56±0.35、10.3±1.03、3.92±1.09(均P<0.05),上述改变以大剂量NaHS组更明显(P<0.05)。
结论：NaHS可能通过抑制TNF-α表达,诱导HSP20表达上调,减少脑梗死体积,从而起到神经保护作用,改善神经功能缺损评分,此作用与剂量相关。图12幅,表5个,参考文献23篇。
第二部分外源性硫化氢对大鼠局灶性脑缺血再灌注损伤的保护机制探讨
目的：通过MAPKs通路探讨外源性硫化氢对局灶性脑缺血再灌注损伤大鼠的神经保护作用机制。
方法：将360只雄性SD大鼠随机分为3组：假手术组,模型组,NaHS (6.4mg/kg)干预组,每组120只,线栓法制备大鼠大脑中动脉栓塞模型,2小时后再灌注,灌注前20分钟给予生理盐水或NaHS腹腔注射,术后6h、24h、48h、3d、7d后行神经功能评分,TTC染色观察脑梗死体积,RT-PCR检测ERK1/2mRNA、P38mRNA和Nrf2mRNA表达,免疫组化与免疫荧光检测p-P38和Nrf2表达,免疫印迹检测海马p-ERK1/2、t-ERK1/2、p-P38、t-P38和Nrf2蛋白表达。
结果：NaHS干预组脑梗死体积和神经功能缺损评分相对于模型组显著减少(P<0.05)；各时刻点ERK1/2mRNA、P38mRNA和Nrf2mRNA的表达干预组较模型组升高(P<0.05)；各时刻点ERK1/2和P38蛋白磷酸化、Nrf2蛋白表达干预组较模型组均升高(P<0.05)。
结论：大鼠脑缺血再灌注损伤后NaHS可能通过诱导ERK1/2和P38蛋白磷酸化,激活下游Nrf2蛋白表达,起到抗氧化应激作用,从而减少脑梗死体积,发挥神经保护作用,改善神经功能缺损。图32幅,表12个,参考文献33篇
Part Ⅰ Neuroprotective mechanism of different concentration of hydrogen sulfide on cerebral ischemia-reperfusion injury in rats
Objective:To investigate the neuro-protective mechanism of exogenous hydrogen sulfide on cerebral ischemia-reperfusion (I/R) in rats.
Methods:A total of288male Sprague-Dawley rats were randomly divided into4groups (n=72),including a sham-operation group (group Ⅰ),an I/R model group (group Ⅱ),a low dose NaHS group (group Ⅲ) and a high dose NaHS group (group Ⅳ). Reversible middle cerebral artery occlusion(MCAO) model was established by intraluminal suture method. However, the rats in sham-operation group were operated on without blockage of the middle cerebral artery. The occlusions in other groups were removed after2h, and20min before the removal of the occlusion,NS,3.2mg/kg NaHS, and6.4mg/kg NaHS were injected into the abdomens of rats in group Ⅱ, Ⅲ, and Ⅳ, respectively. At6h,24h,48h,and7d after the reperfusion,behavioral test was used to evaluate the neurological deficiency, and TTC staining was used to observe volume of cerebral infarction. In addition, the protein expression of heat shock protein20(HSP20) and tumor necrosis factor-alpha(TNF-α) in ischemic cortex were measured by immuno-histochemical method and Western blot.
Results:Compared with I/R group, the neurological deficiency scores and volume of cerebral infarction of the group Ⅲ and Ⅳ were significantly decreased. Furthermore, the protein expression of HSP20in the group Ⅲ, and IV were markedly up-regulated while TNF-a markedly down regulated after the reperfusion.
Conclusion:NaHS may exert anti-necrotic and anti-inflammatory function by inducing the expression of HSP20, inhibiting the expression of TNF-a, and reducing the size of cerebral infarction, and therefore, protecting the neuron after I/R injury.
Part Ⅱ Neuroprotective mechanism of hydrogen sulfide on rats after cerebral ischemia-reperfusion by MAPKs pathway
Objective:To investigate the neuroprotective mechanism of exogenous hydrogen sulfide on rats after cerebral ischemia-reperfusion by MAPKs pathway.
Methods:A total of360Sprague-Dawley male rats were randomly divided into three groups (n=90), including a sham-operation group, an ischemia-reperfusion(I/R) model group, NaHS (6.4mg/kg) group. Reversible middle cerebral artery occlusion(MCAO) model was established by intraluminal suture technique. The rats of sham-operation group were operated on while the middle cerebral artery was not blocked. At6h,24h,48h,3d and7d after the reperfusion, TTC staining was used to observe volume of cerebral infarction. The gene expression of ERK1/2、 P38and Nrf2in the hippocampus was measured by RT-PCR,while the protein expression of p-ERK1/2、t-ERK1/2、p-P38、t-P38and Nrf2was measured by Western blot or immunohistochemical method.
Results:Compared with the I/R group, the volume of cerebral infarction and apoptosis of neurons of NaHS group was significantly lower. The Nrf2protein expression and phosphorylation of ERK1/2and P38in NaHS group increased significantly.
Conclusion:Our animal data suggested that the Nrf2protein expression and the phosphorylation of ERK1/2and P38in the rat ischemic/reperfusion injury brain were decreased strongly after MCAO, NaHS supplement induced and increased significantly relieve the focal cerebral I/R injury, which has anti-oxidative stress effect on the cerebral ischemia-reperfusion injury.
引文
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[48]Bruning CA, Prigol M, Luchese C, et al.Protective effect of diphenyl diselenide on ischemia and reperfusion-induced cerebral injury:involvement of oxidative stress and pro-inflammatory cytokines[J].Neurochem Res,2012,37(10):2249-58.
[49]Zhang P, Li W, Li L, et al.Treatment with edaravone attenuates ischemic brain injury and inhibits neurogenesis in the subventricular zone of adult rats after focal cerebral ischemia and reperfusion injury[J].Neuroscience,2012,201: 297-306.
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[47]Li Y,Chopp M, Jiang N,et al.Induction of DNA fragmentation after 10 to 20 mintes of focal cerebral ischemia in rats [J]. Stroke,1995,26(1-2):1252.
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[1]Martelli A, Testai L, Breschi MC,et al.Hydrogen sulphide:novel opportunity for drug discovery[J].Med Res Rev,2012,32(6):1093-1130.
[2]Ewelina TOWICKA, Jerzy BETTOWSKI. Hydrogen sulfide(H2S)-:the third gas of interest for pharmacologists[J]. Pharmacol Rep,2007,59(1):4-24.
[3]Tang C, Li X, Du J. Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system[J].Curr Vasc Pharmacol,2006,4 (1):17-22.
[4]Li L, Moore P.K. Putative biological roles of hydrogen sulfide in health and disease:a breath of not so fresh air[J].Trends in Pharmacol Sci,2008,29 (2):84-90.
[5]Taoka S, Banerjee R. Characterization of NO binding to human cystathionine beta-synthase:possible implications of the effects of CO and NO binding to the human enzyme[J]. J Inorg Biochem,2001,87:245-251.
[6]Chad K, Nicholson, John W. Calvert. Hydrogen sulfide and ischemia-reperfusion injury[J]. Pharmacol Res,2010,62(4):289-297.
[7]Magierowski M, Jasnos K, Kwiecien S,et al.Role of hydrogen sulfide in the physiology of gastrointestinal tract and in the mechanism of gastroprotection [J].Postepy Hig Med Dosw,2013,6(67):150-156.
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