高压氧和低压缺氧预适应对缺血脑损伤的神经保护作用及机制研究
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摘要
背景和目的:
预先给予机体某种刺激可以使机体产生对有害因素的耐受性或适应性增强,称为预适应(preconditioning)。以往在缺血/低氧预适应(ischemia/hypoxia preconditioning,IP/HP)对缺血性脑损伤的保护作用方面研究较广泛,但缺血/低氧预适应的临床应用受到伦理学限制。因此寻找新的预适应方案非常重要,近来少数研究发现高压氧预适应(hyperbaric oxygen preconditioning,HBOP)对缺血性脑损伤也有保护作用,但其机制不清,且HBOP和低压缺氧预适应(hypobaric hypoxia preconditioning,HHP)对脑保护作用有何异同和优缺点也不清楚。本研究利用家兔右侧大脑中动脉闭塞(middlecerebral artery occlusion,MCAO)模型,观察HBOP和HHP对MCAO家兔行为学、MRI、病理学表现,脑梗塞灶体积,梗塞灶周围局部脑组织氧分压(partial pressure ofbrain tissue oxygen,PbtO_2)及脑组织间液微透析(microdialysis)结果等的影响,比较HBOP和HHP对缺血性脑损伤的神经保护作用,并初步探讨预适应对缺血性脑损伤的神经保护机制。
方法:
1.选择体重2.0～2.5kg,月龄3～4月的雄性家兔72只,随机分为单纯MCAO组,HBOP+MCAO组,HHP+MCAO组,每组24只;
2.采用改良Bederson法建立家兔右侧MCAO模型;
3.动物放入高压氧舱(100%O_2,250Kpa,1hr/d,5d)行HBOP;动物放入低压氧舱(4000m,61.6Kpa,3d)行HHP;
4.分别观察各组家兔MCAO模型制备后第1、3、10及20d的行为学变化、MRI、病理学表现及脑梗塞灶体积;
5.运用LICOX CMP组织氧监测仪动态监测家兔MCAO后第1、3和10d的梗塞灶周围PbtO_2;
6.家兔MCAO后第1、3、10及20d行脑组织间液微透析监测,了解梗塞灶周围脑组织及对侧相应脑区脑组织间液葡萄糖、乳酸、丙酮酸、甘油和谷氨酸浓度。
结果:
1.本实验三组均选择雄性家兔并采用改良Bederson法经眶后入颅制作家兔MCAO模型可靠性强;
2.与单纯MCAO组比较,HBOP+MCAO组和HHP+MCAO组动物的神经功能缺损评分明显降低(P＜0.05),且两种预适应组之间无明显差别;
3.家兔脑MRI检查发现MCAO后不同时相点缺血区T2WI均呈高信号,第1d时高信号较均匀,主要位于右基底节区和右侧大脑半球颞顶叶,三组的信号范围及强度无明显差别;第3d时T2WI高信号范围稍扩大且欠均匀,边界较模糊,平均信号强度增高,但HBOP和HHP组信号强度及范围明显小于单纯MCAO组(P＜0.05);第10d时三组T2WI高信号范围缩小,信号强度降低,多位于顶叶或颞叶,二种预适应组信号范围及强度均显著小于单纯MCAO组(P＜0.05);
4.TTC染色测定MCAO后1d三组家兔大脑基底节区及颞叶部位出现明显梗塞灶,且三组间梗塞灶体积无明显差异;梗塞灶体积在MCAO后第3d达高峰,但HBOP和HHP组明显小于单纯MCAO组(P＜0.05);第10、20d三组梗塞灶体积均明显缩小,且二种预适应组显著小于单纯MCAO组(P＜0.05);
5.病理学结果显示单纯MCAO组可见缺血区脑组织染色苍白,第10d时梗塞灶脑组织崩解成无结构的细颗粒状物,细胞成分少见,神经纤维网呈空泡化;HBOP+MCAO组和HHP+MCAO组第10d时可见缺血坏死周围胶质细胞增生,梗塞灶边界较清楚;
6.HBOP+MCAO组和HHP+MCAO组家兔梗塞灶周围PbtO_2于第1、3和10d均明显高于单纯MCAO组(P＜0.05);并且预适应后PbtO_2水平恢复较不行预适应快;
7.梗塞灶周围脑组织间液微透析分析发现三组家兔MCAO后葡萄糖浓度均持续降低,但HBOP+MCAO和HHP+MCAO组在第3d时已明显恢复,第10d时已基本恢复至基线值且左右侧对比无明显差异,而单纯MCAO组在第10d时才逐渐恢复,第20d时仍低于基线值(P＜0.05),与左侧比较显著降低(P＜0.05),其中在第3d时HHP+MCAO组明显高于单纯MCAO组(P＜0.05);三组家兔乳酸浓度在MCAO后第1d迅速升高达峰值,第3d后开始下降,第20d仍明显高于基线值(P＜0.05);甘油浓度在三组家兔MCAO后第1d升高明显(P＜0.05),以后逐渐降低,单纯MCAO组在第1、3、10和20d各时相点均明显高于预适应组(P＜0.05);三组家兔谷氨酸浓度在MCAO后均持续升高,第3d达峰值,且显著高于对侧(P＜0.05),但HBOP+MCAO组在第1d时仅轻度升高,明显低于HHP+MCAO组和单纯MCAO组(P＜0.05),而在第10d时显著高于HHP+MCAO组和单纯MCAO组(P＜0.05)。
结论:
1.本实验采用的改良Bederson法经眶后入颅制作家兔MCAO模型,MCA阻断确切,模型成功率高,动物存活率高,便于护理,可以较好地模拟临床脑梗塞演变过程;
2.HBOP和HHP能明显改善MCAO家兔神经功能,缩小梗塞灶体积,有一定的神经保护作用,HBOP及HHP的神经保护作用效果无明显差异;
3.HBOP及HHP均能提高家兔MCAO后脑组织梗塞灶周围的PbtO_2;
4.HBOP和HHP均能减轻家兔MCAO梗塞灶周围的能量和神经递质代谢紊乱;
5.梗塞灶周围脑组织间液微透析监测结果支持梗塞灶周围存在“生化半暗带”区域,兴奋性氨基酸毒性作用可能是缺血性脑损伤的重要机制之一,高压氧和低压缺氧预适应改善脑缺血性损伤可能是通过促进“缺血半暗带”或“生化半暗带”的恢复而起作用。
Background and Purposes:
Pretreating with one kind of stimulus can enhance the tolerance of body to impaired factor which called preconditioning.Ischemia and hypoxia preconditioning have been shown their protective advantages on ischemic neuronal damage,but there exists moral problem.Therefore,it is very important to find a new method.The protection of hyperbaric oxygen preconditioning(HBOP) on cerebral ischemia has been demonstrated in few studies,But its mechanism is unclear.More important are the advantages and disadvantages of neuroprotective effects between HBOP and hypobaric hypoxia preconditioning(HHP) remains unclear.Therefore,we designed the following model to make the above problems clear.The right middle cerebral artery occlusion(MCAO) rabbit modle which established by Bederson was used in our prevent experiment to evaluate the neuroprotective effects of HBOP and HHP on cerebral ischemia and determine their mechanisms.,the neurological deficits,signal intensity of magnetic resonance imaging(MRI),pathological changes, infarct size,Pressure of brain tissue oxygen(PbtO2) and in vivo microdialysis around infarcted area were detected in rabbits after permanent MCAO as well as which were treated by HBOP or HHP before MCAO.
Materials and methods:
1.72 male rabbits with body weight 2 to 2.5 kg and age 3 to 4 months were randomly divided into three groups:simple MCAO group(n=24),HBOP+MCAO group(n=24) and HHP+MCAO group(n=24).
2.Before MCAO,preconditioning were performed,the animals in HBOP+MCAO group had been kept in hypobaric hypoxia oxygen chamber for 5d(100%O_2, 250Kpa,1hr/d),while the animals in HHP+MCAO group had been kept in hyperbaric oxygen chamber for 3 d(4000m,61.6Kpa).
3.Then the MCAO model were made according to Bederson's method.
4.The neurological deficits,signal intensity of MRI,pathological changes and infarct size were detected at 1、3、10、20d respectively after permanent MCAO in rabbits of three groups.
5.The PbtO_2 at the edge of the infarcted region was monitored with LICOX CMP tissue oxygen pressure monitor(TOPM) at 1、3、10d after permanent MCAO in rabbits.
6.Microdialysis of interstitial fluid of brain at the edge of infarcted region,including the concentration of glucose,lactate,pyruvate,glutamate were monitored,and the ratio of lactate/pyruvate was calculated.
Results:
1.All animals of the three groups are male and the reliability of MCAO model was well.
2.Compared with simple MCAO group,the score of neurological deficits decreased significantly in HBOP group and HHP group at all time points(1、3、10、20d)(P＜0.05).
3.T2WI of MRI of the animals in three groups were showed High signal around the right temporal and parietal lobes at all time points(1、3、10、20d),Infarcted size and signal intensity reduced at 3 d after permanent MCAO(P＜0.05).Compared with the simple MCAO group,the abnormal signal zones of T2WI in MRI which represented the ischemia and infarcted size were reduced significantly in HBOP group and HHP group at 3、10 d after permanent MCAO.
4.The results of TTC staining indicated infarcted regions appeared in right side of brain after permanent MCAO,there were no statistical differences in the three groups in infarcted size at 1 d,and the infarcted size arrived the top in 3 d after permanent MCAO. Compared with simple MCAO group,size reduced significantly in HBOP+MCAO group and HHP+MCAO group at 3、10、20 d after permanent MCAO(P＜0.05).
5.Pathology at 1d showed that,in the simple MCAO group,the color of cerebral ischemia were white,almostly no normal cell could be seen in infarcted region in 10 d.But clear boundary could be found in HBOP+MCAO group and HHP+MCAO group at 10、20 d after permanent MCAO.
6.PbtO_2 around the infarcted regions in the simple MCAO group significantly decreased at 1、3、10 d after permanent MCAO(P＜0.05),which were significantly increased after HBOP and HHP(P＜0.05).PbtO_2 in preconditioning groups come to normal quicker than simple MCAO group.
7.The variations of the components in the microdialysis fluid from the interstitial brain in the simple MCAO group,HBOP+MCAO group and HHP+MCAO group were not the same. Glucose productions decreased at 1d after MCAO,the two preconditioning groups recovered to normal at 3 d,there were statistically significant between the two preconditioning group and simple MCAO group;while the simple MCAO group still decreased at 20 d and were significantly lower than the left(P＜0.05).The lactate production increased at 1、3d,pyruvate increased at 1、3d, glyceral increased at 1d,there were statistically significant between two preconditioning groups and simple MCAO group.The glutamate concentration increased after MCAO,peaking at 3d,the difference of the glutamate concentration between the HBOP+MCAO group and the other two groups was statistically significant at 1、10d(P＜0.05).
Conclusions:
1.Because of the characteristics of high survival rate and easy to breed,the MCAO model prepared by improved Bederson's method is very useful,and it can imitate the clinical changes of cerebral ischemia.
2.HBOP and HHP can improve neurologic deficits and reduce infarcted volume after permanent MCAO in rabbits.There are no significant differences on the neuroprotective effects of HBOP and HHP on cerebral ischemia.
3.HBOP and HHP can improve the PbtO_2 around the infracted zone after MCAO in rabbits
4.HBOP and HHP can improve the energy metabolism and neurotransimitters disorders around the infracted zone after MCAO in rabbits
5.The variations of the components of the microdialysis interstitial fluid from the brain support the presence of "biochemical penumbra" around the infracted zone after MCAO,which suggested disorders of the toxicities of excitatory amino acids probably be one of the important mechanisms of cerebral ischemia injuries and the neuroprotective effects of HBOP and HHP maybe due to they could facilitate the recovery of "ischemia penumbra" and "biochemical penumbra" around the infracted zone.
预先给予机体某种刺激可以使机体产生对有害因素的耐受性或适应性增强,称为预适应(preconditioning)。以往在缺血/低氧预适应(ischemia/hypoxia preconditioning,IP/HP)对缺血性脑损伤的保护作用方面研究较广泛,但缺血/低氧预适应的临床应用受到伦理学限制。因此寻找新的预适应方案非常重要,近来少数研究发现高压氧预适应(hyperbaric oxygen preconditioning,HBOP)对缺血性脑损伤也有保护作用,但其机制不清,且HBOP和低压缺氧预适应(hypobaric hypoxia preconditioning,HHP)对脑保护作用有何异同和优缺点也不清楚。本研究利用家兔右侧大脑中动脉闭塞(middlecerebral artery occlusion,MCAO)模型,观察HBOP和HHP对MCAO家兔行为学、MRI、病理学表现,脑梗塞灶体积,梗塞灶周围局部脑组织氧分压(partial pressure ofbrain tissue oxygen,PbtO_2)及脑组织间液微透析(microdialysis)结果等的影响,比较HBOP和HHP对缺血性脑损伤的神经保护作用,并初步探讨预适应对缺血性脑损伤的神经保护机制。
方法:
1.选择体重2.0～2.5kg,月龄3～4月的雄性家兔72只,随机分为单纯MCAO组,HBOP+MCAO组,HHP+MCAO组,每组24只;
2.采用改良Bederson法建立家兔右侧MCAO模型;
3.动物放入高压氧舱(100%O_2,250Kpa,1hr/d,5d)行HBOP;动物放入低压氧舱(4000m,61.6Kpa,3d)行HHP;
4.分别观察各组家兔MCAO模型制备后第1、3、10及20d的行为学变化、MRI、病理学表现及脑梗塞灶体积;
5.运用LICOX CMP组织氧监测仪动态监测家兔MCAO后第1、3和10d的梗塞灶周围PbtO_2;
6.家兔MCAO后第1、3、10及20d行脑组织间液微透析监测,了解梗塞灶周围脑组织及对侧相应脑区脑组织间液葡萄糖、乳酸、丙酮酸、甘油和谷氨酸浓度。
结果:
1.本实验三组均选择雄性家兔并采用改良Bederson法经眶后入颅制作家兔MCAO模型可靠性强;
2.与单纯MCAO组比较,HBOP+MCAO组和HHP+MCAO组动物的神经功能缺损评分明显降低(P＜0.05),且两种预适应组之间无明显差别;
3.家兔脑MRI检查发现MCAO后不同时相点缺血区T2WI均呈高信号,第1d时高信号较均匀,主要位于右基底节区和右侧大脑半球颞顶叶,三组的信号范围及强度无明显差别;第3d时T2WI高信号范围稍扩大且欠均匀,边界较模糊,平均信号强度增高,但HBOP和HHP组信号强度及范围明显小于单纯MCAO组(P＜0.05);第10d时三组T2WI高信号范围缩小,信号强度降低,多位于顶叶或颞叶,二种预适应组信号范围及强度均显著小于单纯MCAO组(P＜0.05);
4.TTC染色测定MCAO后1d三组家兔大脑基底节区及颞叶部位出现明显梗塞灶,且三组间梗塞灶体积无明显差异;梗塞灶体积在MCAO后第3d达高峰,但HBOP和HHP组明显小于单纯MCAO组(P＜0.05);第10、20d三组梗塞灶体积均明显缩小,且二种预适应组显著小于单纯MCAO组(P＜0.05);
5.病理学结果显示单纯MCAO组可见缺血区脑组织染色苍白,第10d时梗塞灶脑组织崩解成无结构的细颗粒状物,细胞成分少见,神经纤维网呈空泡化;HBOP+MCAO组和HHP+MCAO组第10d时可见缺血坏死周围胶质细胞增生,梗塞灶边界较清楚;
6.HBOP+MCAO组和HHP+MCAO组家兔梗塞灶周围PbtO_2于第1、3和10d均明显高于单纯MCAO组(P＜0.05);并且预适应后PbtO_2水平恢复较不行预适应快;
7.梗塞灶周围脑组织间液微透析分析发现三组家兔MCAO后葡萄糖浓度均持续降低,但HBOP+MCAO和HHP+MCAO组在第3d时已明显恢复,第10d时已基本恢复至基线值且左右侧对比无明显差异,而单纯MCAO组在第10d时才逐渐恢复,第20d时仍低于基线值(P＜0.05),与左侧比较显著降低(P＜0.05),其中在第3d时HHP+MCAO组明显高于单纯MCAO组(P＜0.05);三组家兔乳酸浓度在MCAO后第1d迅速升高达峰值,第3d后开始下降,第20d仍明显高于基线值(P＜0.05);甘油浓度在三组家兔MCAO后第1d升高明显(P＜0.05),以后逐渐降低,单纯MCAO组在第1、3、10和20d各时相点均明显高于预适应组(P＜0.05);三组家兔谷氨酸浓度在MCAO后均持续升高,第3d达峰值,且显著高于对侧(P＜0.05),但HBOP+MCAO组在第1d时仅轻度升高,明显低于HHP+MCAO组和单纯MCAO组(P＜0.05),而在第10d时显著高于HHP+MCAO组和单纯MCAO组(P＜0.05)。
结论:
1.本实验采用的改良Bederson法经眶后入颅制作家兔MCAO模型,MCA阻断确切,模型成功率高,动物存活率高,便于护理,可以较好地模拟临床脑梗塞演变过程;
2.HBOP和HHP能明显改善MCAO家兔神经功能,缩小梗塞灶体积,有一定的神经保护作用,HBOP及HHP的神经保护作用效果无明显差异;
3.HBOP及HHP均能提高家兔MCAO后脑组织梗塞灶周围的PbtO_2;
4.HBOP和HHP均能减轻家兔MCAO梗塞灶周围的能量和神经递质代谢紊乱;
5.梗塞灶周围脑组织间液微透析监测结果支持梗塞灶周围存在“生化半暗带”区域,兴奋性氨基酸毒性作用可能是缺血性脑损伤的重要机制之一,高压氧和低压缺氧预适应改善脑缺血性损伤可能是通过促进“缺血半暗带”或“生化半暗带”的恢复而起作用。
Background and Purposes:
Pretreating with one kind of stimulus can enhance the tolerance of body to impaired factor which called preconditioning.Ischemia and hypoxia preconditioning have been shown their protective advantages on ischemic neuronal damage,but there exists moral problem.Therefore,it is very important to find a new method.The protection of hyperbaric oxygen preconditioning(HBOP) on cerebral ischemia has been demonstrated in few studies,But its mechanism is unclear.More important are the advantages and disadvantages of neuroprotective effects between HBOP and hypobaric hypoxia preconditioning(HHP) remains unclear.Therefore,we designed the following model to make the above problems clear.The right middle cerebral artery occlusion(MCAO) rabbit modle which established by Bederson was used in our prevent experiment to evaluate the neuroprotective effects of HBOP and HHP on cerebral ischemia and determine their mechanisms.,the neurological deficits,signal intensity of magnetic resonance imaging(MRI),pathological changes, infarct size,Pressure of brain tissue oxygen(PbtO2) and in vivo microdialysis around infarcted area were detected in rabbits after permanent MCAO as well as which were treated by HBOP or HHP before MCAO.
Materials and methods:
1.72 male rabbits with body weight 2 to 2.5 kg and age 3 to 4 months were randomly divided into three groups:simple MCAO group(n=24),HBOP+MCAO group(n=24) and HHP+MCAO group(n=24).
2.Before MCAO,preconditioning were performed,the animals in HBOP+MCAO group had been kept in hypobaric hypoxia oxygen chamber for 5d(100%O_2, 250Kpa,1hr/d),while the animals in HHP+MCAO group had been kept in hyperbaric oxygen chamber for 3 d(4000m,61.6Kpa).
3.Then the MCAO model were made according to Bederson's method.
4.The neurological deficits,signal intensity of MRI,pathological changes and infarct size were detected at 1、3、10、20d respectively after permanent MCAO in rabbits of three groups.
5.The PbtO_2 at the edge of the infarcted region was monitored with LICOX CMP tissue oxygen pressure monitor(TOPM) at 1、3、10d after permanent MCAO in rabbits.
6.Microdialysis of interstitial fluid of brain at the edge of infarcted region,including the concentration of glucose,lactate,pyruvate,glutamate were monitored,and the ratio of lactate/pyruvate was calculated.
Results:
1.All animals of the three groups are male and the reliability of MCAO model was well.
2.Compared with simple MCAO group,the score of neurological deficits decreased significantly in HBOP group and HHP group at all time points(1、3、10、20d)(P＜0.05).
3.T2WI of MRI of the animals in three groups were showed High signal around the right temporal and parietal lobes at all time points(1、3、10、20d),Infarcted size and signal intensity reduced at 3 d after permanent MCAO(P＜0.05).Compared with the simple MCAO group,the abnormal signal zones of T2WI in MRI which represented the ischemia and infarcted size were reduced significantly in HBOP group and HHP group at 3、10 d after permanent MCAO.
4.The results of TTC staining indicated infarcted regions appeared in right side of brain after permanent MCAO,there were no statistical differences in the three groups in infarcted size at 1 d,and the infarcted size arrived the top in 3 d after permanent MCAO. Compared with simple MCAO group,size reduced significantly in HBOP+MCAO group and HHP+MCAO group at 3、10、20 d after permanent MCAO(P＜0.05).
5.Pathology at 1d showed that,in the simple MCAO group,the color of cerebral ischemia were white,almostly no normal cell could be seen in infarcted region in 10 d.But clear boundary could be found in HBOP+MCAO group and HHP+MCAO group at 10、20 d after permanent MCAO.
6.PbtO_2 around the infarcted regions in the simple MCAO group significantly decreased at 1、3、10 d after permanent MCAO(P＜0.05),which were significantly increased after HBOP and HHP(P＜0.05).PbtO_2 in preconditioning groups come to normal quicker than simple MCAO group.
7.The variations of the components in the microdialysis fluid from the interstitial brain in the simple MCAO group,HBOP+MCAO group and HHP+MCAO group were not the same. Glucose productions decreased at 1d after MCAO,the two preconditioning groups recovered to normal at 3 d,there were statistically significant between the two preconditioning group and simple MCAO group;while the simple MCAO group still decreased at 20 d and were significantly lower than the left(P＜0.05).The lactate production increased at 1、3d,pyruvate increased at 1、3d, glyceral increased at 1d,there were statistically significant between two preconditioning groups and simple MCAO group.The glutamate concentration increased after MCAO,peaking at 3d,the difference of the glutamate concentration between the HBOP+MCAO group and the other two groups was statistically significant at 1、10d(P＜0.05).
Conclusions:
1.Because of the characteristics of high survival rate and easy to breed,the MCAO model prepared by improved Bederson's method is very useful,and it can imitate the clinical changes of cerebral ischemia.
2.HBOP and HHP can improve neurologic deficits and reduce infarcted volume after permanent MCAO in rabbits.There are no significant differences on the neuroprotective effects of HBOP and HHP on cerebral ischemia.
3.HBOP and HHP can improve the PbtO_2 around the infracted zone after MCAO in rabbits
4.HBOP and HHP can improve the energy metabolism and neurotransimitters disorders around the infracted zone after MCAO in rabbits
5.The variations of the components of the microdialysis interstitial fluid from the brain support the presence of "biochemical penumbra" around the infracted zone after MCAO,which suggested disorders of the toxicities of excitatory amino acids probably be one of the important mechanisms of cerebral ischemia injuries and the neuroprotective effects of HBOP and HHP maybe due to they could facilitate the recovery of "ischemia penumbra" and "biochemical penumbra" around the infracted zone.
引文
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