间断性复灌干预对缺血脑的保护及其机制研究
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摘要
脑血管疾病已成为中国第二位死亡原因,其中约80%为缺血性疾病。溶栓治疗后脑组织将面临再次损伤,即缺血/复灌损伤(ischemia/reperfusion injury, I/R损伤)。间断性复灌干预(interrupted reperfusion intervention, IRIV)治疗是在复灌初期对复灌血流实施一系列短暂的机械性梗阻和再灌注的方法,已被证明具有神经保护作用,但对其保护机制的研究仍存在诸多空白。
本论文用C57BL/6小鼠,通过手术前后局部脑血流多普勒检测,横杆跑动测试,建立双侧颈总动脉结扎(bilateral common carotid arterial occlusion, BCCAO)20min所导致的小鼠全脑缺血模型。
在该模型上,我们对IRIV干预程序及其治疗时间窗进行了优化,利用横杆跑动、爬杆和水迷宫实验各参数作为评价指标,对3个循环的10s/10s、15s/15s、30s/30s三种不同的夹闭/复灌IRIV程序的神经功能保护作用进行评测,选取最优IRIV干预程序组进行治疗时间窗的的确定。结果显示,15s/15sIRIV程序具有较好的神经功能保护作用,在缺血后的60min内效果较好。
NADPH氧化酶(NADPH oxidase, NOX)是被复灌事件激活的体内重要氧化酶,我们利用NOX抑制剂Apocynin结合IRIV或两种干预单独使用的方式,观察小鼠I/R损伤后在横杆跑动、爬杆和水迷宫实验中的表现,小鼠脑部皮层、海马和纹状体神经元的存活率,脑组织中NOX活性及其重要亚基gp91phox和p47phox的表达,p47phox的转位,以及Racl的活化水平,以探究IRIV是否通过抑制NOX发挥神经保护作用。结果显示, IRIV通过减少p47phox转位,降低NOX的装配,并主要通过降低Racl的活化水平抑制已装配NOX的激活。
复灌后NMDA受体的激活可影响NOX的活性,我们应用脑室给NMDA或MK-801结合IRIV的方式,观察I/R损伤后脑组织中神经元内游离Ca2+浓度,Racl的表达和活化,NOX活性水平,以及NR 2A和NR 2B亚基的表达,以探究IRIV是否通过NMDA受体的激活抑制NOX。结果显示,IRIV可抑制缺血/复灌后NR 2A和NR 2B亚基表达和胞体内游离Ca2+浓度的增高,从而影响Racl活化,抑制NOX活性升高。
为进一步探究NMDA和NOX之间的联系,我们建立离体培养海马神经元氧糖剥夺/复灌(oxygen and glucose deprivation/reperfusion, OGD/RP)模型,应用NMDA受体激动剂NMDA和抑制剂MK-801、经典型PKC (classic PKC, cPKC)激动剂PMA和抑制剂G66983等工具药,观察OGD/RP后神经元内游离Ca2+浓度,Racl, gp91phox和p47phox的表达水平,以及NOX活性水平。结果显示,复灌损伤后NOX活性受NMDAR-Ca2+-cPKC-Racl通路调控。
综上,IRIV可抑制脑缺血/复灌后组织中NOX的激活而发挥神经保护作用,IRIV对NADPH氧化酶的抑制作用涉及对NMDAR-Ca2+-cPKC-Rac 1通路的调控。
Cerebrovascular diseases have become the second cause of death in China, and about 80% are ischemic vascular diseases. Re-establishing perfusion as soon as possible is the clinical goal to minimize ischemic injury, but it also leads to additional damage which is called ischemia/reperfusion (I/R) injury. Interrupted reperfusion intervention (IRIV), which consists of several cycles of brief ischemia and reperfusion followed by permanent reperfusion, is neuroprotective in animal models, but the underlying mechanisms are still unclear.
Based on Doppler measurement of regional cerebral blood flow and the beam walking test, we established a stable global cerebral ischemia model by bilateral common carotid arterial occlusion in C57BL/6 mice.
Then, we evaluated the neuroprotective effects of different IRIV protocols (3 cycles of 10 s/10 s,15 s/15 s,30 s/30s occlusion/reperfusion) and determined the therapeutic time window of the best protocol by behavioral evaluations (beam walking, pole test and Morris water maze). We found that 3 cycles of 15 s occlusion/15 s reperfusion was most protective, and its therapeutic time window was within 60 min. An IRIV of 15 s/15 s decreased the oxidative stress after I/R injury and increased the survival rates of neurons.
NADPH oxidase plays a critical role in the superoxide anion generation which is triggered by the onset of reperfusion. To determine whether NADPH oxidase participates in the neural protection against global I/R injury following IRIV, mice were given IRIV and (or) the NOX inhibitor apocynin, and were evaluated for neurological functional deficits by beam walking, pole test and Morris water maze. Brain tissues were used to measure the expression of gp91phox and p47phox, the translocation of p47phox，the activity of NOX and the activation of Racl. We found that the neuroprotective effect of IRIV was mediated by decreasing the expression and translocation of p47phox, as well as the activation of Racl, and subsequently reduced the assembly and activation of NOX.
The NMDA receptor participates in the activation of NOX. We treated mice with NMDA, MK-801 or vehicle combined with IRIV to determine whether the NMDA receptor participates in the suppression of NOX activity by IRIV. The Ca2+ concentration, the expression and activation of Racl, the activity of NOX and the expression of NR 2A and NR 2B were measured. The results showed that IRIV suppressed NOX activity and this was partly mediated by decreasing the expression of NR 2A and NR 2B, and the activation of the NMDA receptor.
Furthermore, to assess the pathway between the NMDA receptor and NOX, we established an oxygen and glucose deprivation/reperfusion (OGD/RP) model with cultured hippocampal neurons. The neurons were treated with NMDA (activator of the NMDA receptor), MK-801 (inhibitor of the NMDA receptor), PMA (activator of cPKC), Go6983 (inhibitor of cPKC) or vehicle at the beginning of reperfusion, and the Ca2+ concentration, the expression of Racl, gp91phox and p47phox, and the activity of NOX were measured. We found that a novel NMDA receptor-Ca2+in-cPKC-Racl pathway was activated by OGD/RP injury.
In conclusion, IRIV decreases the activation of NOX after global cerebral ischemia/reperfusion injury, which at least though the suppression of the NMDAR-Ca2+-cPKC-Racl pathway.
本论文用C57BL/6小鼠,通过手术前后局部脑血流多普勒检测,横杆跑动测试,建立双侧颈总动脉结扎(bilateral common carotid arterial occlusion, BCCAO)20min所导致的小鼠全脑缺血模型。
在该模型上,我们对IRIV干预程序及其治疗时间窗进行了优化,利用横杆跑动、爬杆和水迷宫实验各参数作为评价指标,对3个循环的10s/10s、15s/15s、30s/30s三种不同的夹闭/复灌IRIV程序的神经功能保护作用进行评测,选取最优IRIV干预程序组进行治疗时间窗的的确定。结果显示,15s/15sIRIV程序具有较好的神经功能保护作用,在缺血后的60min内效果较好。
NADPH氧化酶(NADPH oxidase, NOX)是被复灌事件激活的体内重要氧化酶,我们利用NOX抑制剂Apocynin结合IRIV或两种干预单独使用的方式,观察小鼠I/R损伤后在横杆跑动、爬杆和水迷宫实验中的表现,小鼠脑部皮层、海马和纹状体神经元的存活率,脑组织中NOX活性及其重要亚基gp91phox和p47phox的表达,p47phox的转位,以及Racl的活化水平,以探究IRIV是否通过抑制NOX发挥神经保护作用。结果显示, IRIV通过减少p47phox转位,降低NOX的装配,并主要通过降低Racl的活化水平抑制已装配NOX的激活。
复灌后NMDA受体的激活可影响NOX的活性,我们应用脑室给NMDA或MK-801结合IRIV的方式,观察I/R损伤后脑组织中神经元内游离Ca2+浓度,Racl的表达和活化,NOX活性水平,以及NR 2A和NR 2B亚基的表达,以探究IRIV是否通过NMDA受体的激活抑制NOX。结果显示,IRIV可抑制缺血/复灌后NR 2A和NR 2B亚基表达和胞体内游离Ca2+浓度的增高,从而影响Racl活化,抑制NOX活性升高。
为进一步探究NMDA和NOX之间的联系,我们建立离体培养海马神经元氧糖剥夺/复灌(oxygen and glucose deprivation/reperfusion, OGD/RP)模型,应用NMDA受体激动剂NMDA和抑制剂MK-801、经典型PKC (classic PKC, cPKC)激动剂PMA和抑制剂G66983等工具药,观察OGD/RP后神经元内游离Ca2+浓度,Racl, gp91phox和p47phox的表达水平,以及NOX活性水平。结果显示,复灌损伤后NOX活性受NMDAR-Ca2+-cPKC-Racl通路调控。
综上,IRIV可抑制脑缺血/复灌后组织中NOX的激活而发挥神经保护作用,IRIV对NADPH氧化酶的抑制作用涉及对NMDAR-Ca2+-cPKC-Rac 1通路的调控。
Cerebrovascular diseases have become the second cause of death in China, and about 80% are ischemic vascular diseases. Re-establishing perfusion as soon as possible is the clinical goal to minimize ischemic injury, but it also leads to additional damage which is called ischemia/reperfusion (I/R) injury. Interrupted reperfusion intervention (IRIV), which consists of several cycles of brief ischemia and reperfusion followed by permanent reperfusion, is neuroprotective in animal models, but the underlying mechanisms are still unclear.
Based on Doppler measurement of regional cerebral blood flow and the beam walking test, we established a stable global cerebral ischemia model by bilateral common carotid arterial occlusion in C57BL/6 mice.
Then, we evaluated the neuroprotective effects of different IRIV protocols (3 cycles of 10 s/10 s,15 s/15 s,30 s/30s occlusion/reperfusion) and determined the therapeutic time window of the best protocol by behavioral evaluations (beam walking, pole test and Morris water maze). We found that 3 cycles of 15 s occlusion/15 s reperfusion was most protective, and its therapeutic time window was within 60 min. An IRIV of 15 s/15 s decreased the oxidative stress after I/R injury and increased the survival rates of neurons.
NADPH oxidase plays a critical role in the superoxide anion generation which is triggered by the onset of reperfusion. To determine whether NADPH oxidase participates in the neural protection against global I/R injury following IRIV, mice were given IRIV and (or) the NOX inhibitor apocynin, and were evaluated for neurological functional deficits by beam walking, pole test and Morris water maze. Brain tissues were used to measure the expression of gp91phox and p47phox, the translocation of p47phox，the activity of NOX and the activation of Racl. We found that the neuroprotective effect of IRIV was mediated by decreasing the expression and translocation of p47phox, as well as the activation of Racl, and subsequently reduced the assembly and activation of NOX.
The NMDA receptor participates in the activation of NOX. We treated mice with NMDA, MK-801 or vehicle combined with IRIV to determine whether the NMDA receptor participates in the suppression of NOX activity by IRIV. The Ca2+ concentration, the expression and activation of Racl, the activity of NOX and the expression of NR 2A and NR 2B were measured. The results showed that IRIV suppressed NOX activity and this was partly mediated by decreasing the expression of NR 2A and NR 2B, and the activation of the NMDA receptor.
Furthermore, to assess the pathway between the NMDA receptor and NOX, we established an oxygen and glucose deprivation/reperfusion (OGD/RP) model with cultured hippocampal neurons. The neurons were treated with NMDA (activator of the NMDA receptor), MK-801 (inhibitor of the NMDA receptor), PMA (activator of cPKC), Go6983 (inhibitor of cPKC) or vehicle at the beginning of reperfusion, and the Ca2+ concentration, the expression of Racl, gp91phox and p47phox, and the activity of NOX were measured. We found that a novel NMDA receptor-Ca2+in-cPKC-Racl pathway was activated by OGD/RP injury.
In conclusion, IRIV decreases the activation of NOX after global cerebral ischemia/reperfusion injury, which at least though the suppression of the NMDAR-Ca2+-cPKC-Racl pathway.
引文
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