CTMP在七氟醚预处理神经保护中的作用机制研究
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摘要
缺血性脑卒中是人类的第二大死因[1]，而目前唯一被FDA批准的外源性输入tPA溶栓，因治疗时间窗窄、副作用多，仅对5%的脑卒中患者显示出确切疗效[2]。预处理可激活多种内源性信号，诱导缺血耐受。以预处理为手段，明确内源性保护信号的关键分子，将为临床脑保护策略研究提供切实可行的新靶点。我科以往的研究发现：七氟醚预处理可诱导脑缺血耐受[3,4]，然而，七氟醚预处理的机制远未阐明。脑缺血损伤后，各种损伤因子如兴奋性氨基酸等大量增加。为了存活，机体同时会激发一系列的保护机制，其中内源性生存信号通路是最重要的一个方面。包括缺血预处理等诸多神经保护策略，也涉及到生存信号Akt的激活[5-7]。但是，在缺血状态下，Akt激酶的磷酸化水平虽然也会增加，神经元却依旧凋亡、坏死——机体本身所活化的Akt通路没能显示出任何的促生存作用[8,9]。这一现象提示：在缺血损伤状态下，可能同时伴有某些负性调控因子激增，致使Akt激酶虽有改变而无活性。2009年Nature Neuroscience上的一篇研究显示：负性调控因子carboxy-terminal modulatorprotein (CTMP)在脑缺血损伤后大量增加[10]。由此，我们推测：七氟醚预处理通过调节CTMP的表达水平，可以恢复Akt激酶活性，从而诱导脑缺血耐受。
本研究旨在揭示CTMP在七氟醚预处理诱导脑缺血耐受中的关键地位及其具体作用机制，为阐明七氟醚预处理诱导脑缺血耐受提供新的学术见解，为临床围术期脑保护策略研究提供新的方向。
实验一七氟醚预处理对大鼠局灶性脑缺血损伤具有神经保护作用
方法：由第四军医大学实验动物中心提供的清洁级雄性40只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为5组Sham组、I/R（ischemia/reperfusion）24h组、PC+I/R（sevoflurane preconditioning+ischemia/reperfusion）24h组、I/R7d组和PC+I/R7d组（Sham=4，其余n=9）。除假手术组（Sham）动物外，所有动物均行局灶性脑缺血再灌注损伤（middle cerebral artery occlusion，MCAO模型），缺血时间为1h，再灌注24h或7d。其中，给予七氟醚预处理的动物（PC+I/R24h组及PC+I/R7d组），在缺血前1h给予2.7%的七氟醚预处理45min。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。分别于再灌注24h和7d观察神经功能学评分（NBS）。评分后，处死动物，取脑，行TTC染色，计算脑梗死容积百分比。
结果：单次七氟醚预处理可显著改善缺血后1d、7d时脑梗死容积百分比，对1d后的神经行为学亦有改善作用。
实验二PI3K/Akt信号通路参与到七氟醚预处理的神经保护作用之中
方法：由第四军医大学实验动物中心提供的清洁级雄性85只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为9组（Sham=5，其余n=10）：Sham组，I/R组，PC+I/R，WT+PC+I/R（wortmannin，WT）组，LY+PC+I/R（LY294002，LY）组，WT+I/R组，LY+I/R组，VE-WT+PC+I/R组和VE-LY+PC+I/R组（两组溶剂对照组，Vehicle，VE）。除假手术组（Sham）动物外，所有动物均行局灶性脑缺血再灌注损伤（MCAO模型），缺血时间为1h，再灌注24h。其中，给予七氟醚预处理的动物，即：PC+I/R组，WT+PC+I/R组，LY+PC+I/R组，VE-WT+PC+I/R组和VE-LY+PC+I/R组，在缺血前1h给予2.7%的七氟醚预处理45min。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。抑制剂WT或LY294002于缺血前10min给予。神经功能评分和脑梗死容积染色于再灌注24h后实施。
结果：Akt信号通路的两种抑制剂均可减少七氟醚预处理的于再灌注24h后的神经保护效果。
实验三七氟醚预处理可抑制CTMP激增，提高Akt激酶活性
方法：65只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为Sham组，I/R组，PC组（单纯预处理组）和PC+I/R组。I/R组动物行局灶性脑缺血再灌注损伤，缺血时间为1h，再灌注24h。PC组和PC+I/R组动物，给予2.7%的七氟醚预处理45min。PC+I/R组动物预处理后1h行MCAO模型。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。PC组，I/R组和PC+I/R组动物分别于再灌注1h，3h，12h和24h后取皮层半暗带。以Western Blot方法检测不同时间点：Akt在Ser473位点磷酸化（pSer473-Akt）水平、其下游直接作用分子GSK3β在Ser9位点的磷酸化（pSer9-GSK3β）水平以及Akt内源性抑制剂CTMP的表达水平。另取16只雄性SD大鼠，应用试剂盒分别检测Sham组，I/R组，PC组及PC+IR组于再灌注3h及相应的预处理时间点缺血半暗带或相应部位组织内Akt激酶活性。。
结果：与Sham组相比，再灌注3h后I/R组，PC组及PC+I/R组的pSer473-Akt水平均显著增加，但pSer9-GSK3β只有在PC组及PC+I/R组增加。I/R组CTMP水平在持续增高至再灌注24h，而I/R组内Akt激酶活性与Sham组间无统计学差异。与I/R组相比，预处理可降低过量增加的pSer-473Akt，但可提高pSer9-GSK3β的表达水平。PC+I/R组CTMP水平较I/R组明显降低并维持至再灌注24h，Akt激酶活性增高。
实验四CTMP过表达可抑制七氟醚预处理的神经保护效果
方法：84只SD大鼠（200到250g)，经过一周适应性饲养后，通过慢病毒转染（lentiviral transduction，LV）方法，于预处理前3d，经侧脑室分别注射LV-CTMP或其乱序对照LV-C。72h后，分析Sham组、LV-CTMP组与LV-C组（n=4）大鼠脑内CTMP的表达状况，及Akt激酶功能活性。另取一批动物，按实验一的方案，于再灌注24h后，对Sham组、LV-CTMP组、LV-C组、I/R组、PC+I/R组、LV-CTMP+PC+I/R组、LV-C+PC+I/R组、LV-CTMP+I/R组和LV-C+I/R组（n=8）动物进行神经功能学评分。Sham组、I/R组、PC+I/R组、LV-CTMP+PC+I/R组、LV-C+PC+I/R组、LV-CTMP+I/R组和LV-C+I/R组在评分后行TTC染色，测量脑梗死容积百分比。
结果：LV-CTMP侧脑室注射3d后CTMP表达含量增加，Akt激酶活性降低。与PC+I/R组相比，CTMP过表达降低了再灌注24h后的神经功能学评分并增加了脑梗死容积百分比，与I/R组动物间没有统计学差异。
It has been confirmed that dysregulation of the pro-survival signal Akt contributes toneuronal damage after ischemic stroke. Neuroprotective strategies such as ischemicpreconditioning and sevoflurane postconditioning promote neuronal survival by activatingAkt[5-7]. A robust increase of phosphorylation level of Akt occurred after ischemiaparalleling its sustained poor function in phosphorylating the downstream pro-apoptoticsubstrates[8,9]. Such data indicate that the phosphorylation level of Akt is not alwaysparallel with its activity. The endogenous inhibitor of Akt, carboxy-terminal modulatorprotein (CTMP)[11], increased robustly after ischemia, it probably participates in thedamage to neurons in the ischemic stroke and be regulated by sevofluranepreconditioning.
The current study was designed to explore the role and mechanism of CTMP inischemic tolerance induced sevoflurane preconditioning, improving our understanding ofsevoflurane preconditioning and providing evidence of new research direction for the
Experiment1Single sevoflurane preconditioning induced neuroprotection
against focal cerebral ischemia and reperfusion injuryMethod：To determine the neuroprotection of single sevoflurane preconditioning，40SD rats were random assigned to5groups: a sham operation group (Sham), anischemia/reperfusion (I/R) group observed24h, a sevoflurane preconditioning (PC+I/R)group observed24h, an I/R group observed7d and a PC+I/R group observed7d (Sham=4;others, n=9). Preconditioned animals were exposed to2.7%sevoflurane for45mins at1hbefore ischemia. The neurological deficits and infarct volumes of the rats were evaluated24h or7d after reperfusion by a researcher blinded to the animal groups.
Result：Sevoflurane preconditioning significantly reduced the infarct volume of therats suffering focal cerebral ischemia at24h and7d after reperfusion, and amelioratedneurological dysfunction at24h after reperfusion.
Experiment2Akt pathway was involved in the neuroprotection of sevofluranepreconditioning
Method：To investigate the role of Akt in the induction of ischemic tolerance bysevoflurane preconditioning, we randomly assigned85rats to9groups: a Sham group(n=5), an I/R group, a PC+I/R group, a sevoflurane preconditioning with wortmannin(WT+PC+I/R) group, a sevoflurane preconditioning with LY294002(LY+PC+I/R) group,an ischemia with wortmannin (WT+I/R) group, an ischemia with LY294002(LY+I/R)group and two vehicle (VE-WT+PC+I/R and VE-LY+PC+I/R) groups. Preconditionedanimals were exposed to2.7%sevoflurane for45mins at1h before ischemia. Theneurological deficits and infarct volumes of the rats were evaluated24h after reperfusionby a researcher blinded to the animal groups. Wortmannin and LY294002wereadministered to the rats10mins before preconditioning. An equal volume of vehicle wasadministered to the rats in the same manner in the VE-WT+PC+I/R and theVE-LY+PC+I/R group.
Result： Wortmannin and LY294002injection lessened the neuroprotection of
sevoflurane preconditioning.
Experiment3Sevoflurane preconditioning suppressed the CTMPover-expression induced by ischemia injury and restored Akt activity
Method： To determine the effect of sevoflurane preconditioning on thephosphorylation levels of Akt and its downstream target GSK3β, as well as changes inCTMP levels and the activity of Akt kinase after ischemia,64rats were random assignedto Sham, I/R, PC or PC+I/R group. Preconditioned animals not subjected to ischemia(noted as0h) were sacrificed24h after preconditioning. Rats in the I/R and PC+I/Rgroups were sacrificed1,3,12and24h after reperfusion (n=5). Akt activity wasdetermined3h after reperfusion with another16SD male rats (n=4).
Result：Ischemia induced a transient increase in the phosphorylation of Akt at Ser473(pSer473-Akt), whereas sevoflurane preconditioning suppressed the phosphorylation ofAkt elicited by ischemia3h after reperfusion. Phosphorylation level of GSK3β(pSer9-GSK3β), a downstream target of Akt, was higher in the PC+I/R group compared tothe I/R group at1h and3h after reperfusion. An Akt kinase activity assay showed thatsevoflurane preconditioning increased Akt activity3h after reperfusion, which wasconsistent with the increased pSer9-GSK3β expression in vivo. Expression of CTMP inthe rats of the I/R group began to increase3h after ischemia/reperfusion and remainedhigher than that of the sham group at24h. Sevoflurane preconditioning suppressed theincrease in CTMP expression induced by I/R injury.
Experiment4CTMP over-expression by LV-CTMP markedly suppressed thebeneficial effects of sevoflurane preconditioning
Method：To examine the effect of CTMP in sevoflurane preconditioning andischemia/reperfusion, we used lentiviral transduction (LV) to increase the expression ofCTMP before preconditioning. Rats received an intracerebroventricular injection of eitherLV-CTMP or LV-C (scrambled control vector)3d before preconditioning. After24h ofreperfusion, rats were subjected to evaluation of neurologic scores and sacrificed to determine infarct volume. Expression of CTMP and the activity of Akt kinase in theLV-CTMP, LV-C and sham operation groups was examined by Western Blot analysis.
Result：Injection of LV-CTMP led to an approximately3-fold increase of CTMPprotein expression and a suppression of Akt kinase activity in the targeted brain regions.CTMP over-expression markedly lessened the beneficial effects of sevofluranepreconditioning.
本研究旨在揭示CTMP在七氟醚预处理诱导脑缺血耐受中的关键地位及其具体作用机制，为阐明七氟醚预处理诱导脑缺血耐受提供新的学术见解，为临床围术期脑保护策略研究提供新的方向。
实验一七氟醚预处理对大鼠局灶性脑缺血损伤具有神经保护作用
方法：由第四军医大学实验动物中心提供的清洁级雄性40只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为5组Sham组、I/R（ischemia/reperfusion）24h组、PC+I/R（sevoflurane preconditioning+ischemia/reperfusion）24h组、I/R7d组和PC+I/R7d组（Sham=4，其余n=9）。除假手术组（Sham）动物外，所有动物均行局灶性脑缺血再灌注损伤（middle cerebral artery occlusion，MCAO模型），缺血时间为1h，再灌注24h或7d。其中，给予七氟醚预处理的动物（PC+I/R24h组及PC+I/R7d组），在缺血前1h给予2.7%的七氟醚预处理45min。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。分别于再灌注24h和7d观察神经功能学评分（NBS）。评分后，处死动物，取脑，行TTC染色，计算脑梗死容积百分比。
结果：单次七氟醚预处理可显著改善缺血后1d、7d时脑梗死容积百分比，对1d后的神经行为学亦有改善作用。
实验二PI3K/Akt信号通路参与到七氟醚预处理的神经保护作用之中
方法：由第四军医大学实验动物中心提供的清洁级雄性85只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为9组（Sham=5，其余n=10）：Sham组，I/R组，PC+I/R，WT+PC+I/R（wortmannin，WT）组，LY+PC+I/R（LY294002，LY）组，WT+I/R组，LY+I/R组，VE-WT+PC+I/R组和VE-LY+PC+I/R组（两组溶剂对照组，Vehicle，VE）。除假手术组（Sham）动物外，所有动物均行局灶性脑缺血再灌注损伤（MCAO模型），缺血时间为1h，再灌注24h。其中，给予七氟醚预处理的动物，即：PC+I/R组，WT+PC+I/R组，LY+PC+I/R组，VE-WT+PC+I/R组和VE-LY+PC+I/R组，在缺血前1h给予2.7%的七氟醚预处理45min。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。抑制剂WT或LY294002于缺血前10min给予。神经功能评分和脑梗死容积染色于再灌注24h后实施。
结果：Akt信号通路的两种抑制剂均可减少七氟醚预处理的于再灌注24h后的神经保护效果。
实验三七氟醚预处理可抑制CTMP激增，提高Akt激酶活性
方法：65只SD大鼠（200到250g)，经过一周适应性饲养后，随机分为Sham组，I/R组，PC组（单纯预处理组）和PC+I/R组。I/R组动物行局灶性脑缺血再灌注损伤，缺血时间为1h，再灌注24h。PC组和PC+I/R组动物，给予2.7%的七氟醚预处理45min。PC+I/R组动物预处理后1h行MCAO模型。Sham组动物实施同样的各项操作，但不诱导脑缺血再灌注损伤，手术操作前1h给予45min纯氧。PC组，I/R组和PC+I/R组动物分别于再灌注1h，3h，12h和24h后取皮层半暗带。以Western Blot方法检测不同时间点：Akt在Ser473位点磷酸化（pSer473-Akt）水平、其下游直接作用分子GSK3β在Ser9位点的磷酸化（pSer9-GSK3β）水平以及Akt内源性抑制剂CTMP的表达水平。另取16只雄性SD大鼠，应用试剂盒分别检测Sham组，I/R组，PC组及PC+IR组于再灌注3h及相应的预处理时间点缺血半暗带或相应部位组织内Akt激酶活性。。
结果：与Sham组相比，再灌注3h后I/R组，PC组及PC+I/R组的pSer473-Akt水平均显著增加，但pSer9-GSK3β只有在PC组及PC+I/R组增加。I/R组CTMP水平在持续增高至再灌注24h，而I/R组内Akt激酶活性与Sham组间无统计学差异。与I/R组相比，预处理可降低过量增加的pSer-473Akt，但可提高pSer9-GSK3β的表达水平。PC+I/R组CTMP水平较I/R组明显降低并维持至再灌注24h，Akt激酶活性增高。
实验四CTMP过表达可抑制七氟醚预处理的神经保护效果
方法：84只SD大鼠（200到250g)，经过一周适应性饲养后，通过慢病毒转染（lentiviral transduction，LV）方法，于预处理前3d，经侧脑室分别注射LV-CTMP或其乱序对照LV-C。72h后，分析Sham组、LV-CTMP组与LV-C组（n=4）大鼠脑内CTMP的表达状况，及Akt激酶功能活性。另取一批动物，按实验一的方案，于再灌注24h后，对Sham组、LV-CTMP组、LV-C组、I/R组、PC+I/R组、LV-CTMP+PC+I/R组、LV-C+PC+I/R组、LV-CTMP+I/R组和LV-C+I/R组（n=8）动物进行神经功能学评分。Sham组、I/R组、PC+I/R组、LV-CTMP+PC+I/R组、LV-C+PC+I/R组、LV-CTMP+I/R组和LV-C+I/R组在评分后行TTC染色，测量脑梗死容积百分比。
结果：LV-CTMP侧脑室注射3d后CTMP表达含量增加，Akt激酶活性降低。与PC+I/R组相比，CTMP过表达降低了再灌注24h后的神经功能学评分并增加了脑梗死容积百分比，与I/R组动物间没有统计学差异。
It has been confirmed that dysregulation of the pro-survival signal Akt contributes toneuronal damage after ischemic stroke. Neuroprotective strategies such as ischemicpreconditioning and sevoflurane postconditioning promote neuronal survival by activatingAkt[5-7]. A robust increase of phosphorylation level of Akt occurred after ischemiaparalleling its sustained poor function in phosphorylating the downstream pro-apoptoticsubstrates[8,9]. Such data indicate that the phosphorylation level of Akt is not alwaysparallel with its activity. The endogenous inhibitor of Akt, carboxy-terminal modulatorprotein (CTMP)[11], increased robustly after ischemia, it probably participates in thedamage to neurons in the ischemic stroke and be regulated by sevofluranepreconditioning.
The current study was designed to explore the role and mechanism of CTMP inischemic tolerance induced sevoflurane preconditioning, improving our understanding ofsevoflurane preconditioning and providing evidence of new research direction for the
Experiment1Single sevoflurane preconditioning induced neuroprotection
against focal cerebral ischemia and reperfusion injuryMethod：To determine the neuroprotection of single sevoflurane preconditioning，40SD rats were random assigned to5groups: a sham operation group (Sham), anischemia/reperfusion (I/R) group observed24h, a sevoflurane preconditioning (PC+I/R)group observed24h, an I/R group observed7d and a PC+I/R group observed7d (Sham=4;others, n=9). Preconditioned animals were exposed to2.7%sevoflurane for45mins at1hbefore ischemia. The neurological deficits and infarct volumes of the rats were evaluated24h or7d after reperfusion by a researcher blinded to the animal groups.
Result：Sevoflurane preconditioning significantly reduced the infarct volume of therats suffering focal cerebral ischemia at24h and7d after reperfusion, and amelioratedneurological dysfunction at24h after reperfusion.
Experiment2Akt pathway was involved in the neuroprotection of sevofluranepreconditioning
Method：To investigate the role of Akt in the induction of ischemic tolerance bysevoflurane preconditioning, we randomly assigned85rats to9groups: a Sham group(n=5), an I/R group, a PC+I/R group, a sevoflurane preconditioning with wortmannin(WT+PC+I/R) group, a sevoflurane preconditioning with LY294002(LY+PC+I/R) group,an ischemia with wortmannin (WT+I/R) group, an ischemia with LY294002(LY+I/R)group and two vehicle (VE-WT+PC+I/R and VE-LY+PC+I/R) groups. Preconditionedanimals were exposed to2.7%sevoflurane for45mins at1h before ischemia. Theneurological deficits and infarct volumes of the rats were evaluated24h after reperfusionby a researcher blinded to the animal groups. Wortmannin and LY294002wereadministered to the rats10mins before preconditioning. An equal volume of vehicle wasadministered to the rats in the same manner in the VE-WT+PC+I/R and theVE-LY+PC+I/R group.
Result： Wortmannin and LY294002injection lessened the neuroprotection of
sevoflurane preconditioning.
Experiment3Sevoflurane preconditioning suppressed the CTMPover-expression induced by ischemia injury and restored Akt activity
Method： To determine the effect of sevoflurane preconditioning on thephosphorylation levels of Akt and its downstream target GSK3β, as well as changes inCTMP levels and the activity of Akt kinase after ischemia,64rats were random assignedto Sham, I/R, PC or PC+I/R group. Preconditioned animals not subjected to ischemia(noted as0h) were sacrificed24h after preconditioning. Rats in the I/R and PC+I/Rgroups were sacrificed1,3,12and24h after reperfusion (n=5). Akt activity wasdetermined3h after reperfusion with another16SD male rats (n=4).
Result：Ischemia induced a transient increase in the phosphorylation of Akt at Ser473(pSer473-Akt), whereas sevoflurane preconditioning suppressed the phosphorylation ofAkt elicited by ischemia3h after reperfusion. Phosphorylation level of GSK3β(pSer9-GSK3β), a downstream target of Akt, was higher in the PC+I/R group compared tothe I/R group at1h and3h after reperfusion. An Akt kinase activity assay showed thatsevoflurane preconditioning increased Akt activity3h after reperfusion, which wasconsistent with the increased pSer9-GSK3β expression in vivo. Expression of CTMP inthe rats of the I/R group began to increase3h after ischemia/reperfusion and remainedhigher than that of the sham group at24h. Sevoflurane preconditioning suppressed theincrease in CTMP expression induced by I/R injury.
Experiment4CTMP over-expression by LV-CTMP markedly suppressed thebeneficial effects of sevoflurane preconditioning
Method：To examine the effect of CTMP in sevoflurane preconditioning andischemia/reperfusion, we used lentiviral transduction (LV) to increase the expression ofCTMP before preconditioning. Rats received an intracerebroventricular injection of eitherLV-CTMP or LV-C (scrambled control vector)3d before preconditioning. After24h ofreperfusion, rats were subjected to evaluation of neurologic scores and sacrificed to determine infarct volume. Expression of CTMP and the activity of Akt kinase in theLV-CTMP, LV-C and sham operation groups was examined by Western Blot analysis.
Result：Injection of LV-CTMP led to an approximately3-fold increase of CTMPprotein expression and a suppression of Akt kinase activity in the targeted brain regions.CTMP over-expression markedly lessened the beneficial effects of sevofluranepreconditioning.
引文
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