磷酸肌酸钠对缺氧窒息幼鼠脑组织中NO、CaM水平及HIF-1amRNA表达的影响
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摘要
背景和目的
缺氧是由多种原因所致的循环血中氧分压或氧含量下降而导致组织细胞供氧不足的病理状态。而中枢神经系统是机体所有组织器官中对缺氧表现最为敏感的部位,易引起脑细胞水肿、变性、坏死,导致神经系统疾病,且脑损伤的严重程度与缺氧程度密切相关。而对于儿科常见缺氧性疾病如新生儿窒息(Asphyxia of newborn)、新生儿缺氧缺血性脑病(Hypoxic-ischemic encephalopathy, HIE)等,则易导致患儿惊厥、运动不协调或障碍、智力低下、学习记忆能力受损,严重者引起脑瘫甚至死亡,不仅对家庭和社会带来沉重的精神压力,也带来了难以负荷的经济负担。
能量代谢障碍是脑组织缺氧后最早发生的病理生理学改变,其后发生的一系列“瀑布样”反应,如氧自由基生成的增加,Ca2+大量内流等,相应引起一氧化氮(Nitric oxide, NO)及钙调蛋白(Calmodulin, CaM)含量的增加,导致神经细胞的变性坏死。而缺氧诱导因子-1a(Hypoxia-inducible factor-1alpha, HIF-1a)作为缺氧调节的重要因子,是目前研究比较广泛的在缺氧性脑损伤中通过调节多种靶基因的表达,从而发挥对神经元的保护作用。磷酸肌酸是由磷酸与肌酸组成的高能磷酸化合物,它是高能磷酸基的暂时贮存形式,其分子中存在氮-磷键,水解后可释放高能量,而且能够在高能量转换的细胞中通过ADP-ATP途径补充机体所需能量,因此既可作为一能量缓冲剂,又可以作为细胞内的能量载体。目前,外源性磷酸肌酸钠(Creatine Phosphate Sodium, PCr)作为一种高效低毒的心肌保护药,已经广泛应用于治疗病毒性心肌炎、心力衰竭等疾病,具有较好疗效,并且作为心脏手术中停搏液的附加成分之一,已被英国马丁代尔大药典收集；近年来有研究显示,PCr同时具有保护、修复神经元的作作,有临床资料显示,PCr可以减轻新生儿缺氧缺血性脑病、脑梗死等疾病的脑损伤程度,但是否通过影响某些因子的变化而发挥促进脑损伤修复或抑制脑细胞变性坏死的发生的相关动物实验室资料报导较少。本课题旨在从动物实验的角度初步探讨幼鼠缺氧后脑组织NO、CaM含量、HIF-1a mRNA的表达在磷酸肌酸钠干预下的变化,为该药的临床应用提供实验室支持。
材料和方法
1实验动物和分组
将75只SD幼鼠随机分为3组,磷酸肌酸钠治疗组(PCr组)25只,生理盐水模型组(NS组)25只,正常对照组25只,其中PCr组和NS组制作缺氧模型,正常对照组不作缺氧处理。
2药物应用
PCr组在幼鼠缺氧前0.5h、缺氧后即刻、24h及48h以1.4mg/g的剂量腹腔注射PCr, NS组在相同时间点腹腔注射等量的生理盐水。正常对照组不注射任何药物。
3标本采集
各组于缺氧后6h各取10只幼鼠,断头取脑,取一半脑组织置于多聚甲醛中固定24h,作病理切片备用；另一半脑组织置于-80℃冰箱中保存,作HIF-1amRNA表达的相对含量测定；各组于末次腹腔注射药物后各取15只幼鼠,断头取脑、称重,置于-80℃冰箱中保存,作NO、CaM含量测定。
4统计学分析
采用SPSS17.0进行分析。标准缺氧耐受时间采用独立样本T检验,NO、CaM含量及HIF-1a mRNA表达的相对含量的组间比较采用单因素方差分析(one-way ANOVA); LSD-t检验用于各组间的两两比较,以P<0.05为差异具有统计学意义。
结果
1与NS组(7.15±0.90)相比,PCr组(7.97±0.75)标准耐受时间明显延长,P<0.05。
2病理学改变：PCr组较NS组神经细胞破坏减少,水肿、坏死明显减轻,炎症细胞浸润较少。
3PCr组[(0.73±0.13)umol/g]的NO含量较正常对照组[(0.55±0.07)umol/g]稍高(P<0.05),但较NS组[(0.86±0.17)umol/g]有所降低(P<0.05)。
4PCr组[(41.19±1.13)ng/L]的CaM含量较正常对照组[(39.56±0.86)ng/L]稍高(P<0.05),但较NS组[(42.04±0.76)ng/L]有所降低(P<0.05)。
5正常对照组(0.04±0.01)几乎无HIF-1a mRNA表达,NS组(1.09±0.01)表达有所增加(P<0.01),PCr组(1.00±0.02)较NS组表达增加更为明显(P<0.05)。
结论
外源性PCr可以延长缺氧幼鼠标准缺氧耐受时间,明显减轻缺氧组幼鼠脑组织的病理学改变,显著降低缺氧组幼鼠NO、CaM含量,增加缺氧组幼鼠HIF-1amRNA的表达,从而发挥神经保护作用。
Background and objectives
Anoxia is the pathological state of low ventilation in tissue and cell,which is caused by the decrease of oxygen partial pressure or oxygen content in the circulation of blood by various reasons. In all organs of the body, the central nervous system is the most sensitive to the anoxia, which causes brain cells edema, degeneration and necrosis easily, even causes nerve systemic diseases.The common diseases in pediatric such as neonatal asphyxia of newborn and newborns hypoxic-ischemic encephalopathy (HIE) cause the children convulsions,the movement out of coordination or obstacles,hypophrenia and impaired ability of learning and memory, seriously cause cerebral palsy and even death. All that bring about heavy pressure and economic burden to the family and society.
Energy metabolization obstacle is the earliest pathological physiology change after anoxia in the brain,then produces a series of "waterfall" responses such as increase of the oxygen radical, excessive influx of calcium, and so on, corresponding causes increase of the nitric oxide(NO) and Calmodulin (CaM).These responses can cause degeneration and necrosis for nerve cells. As the important factor of oxygen adjustment, at present hypoxia-inducible factor1alpha (HIF-1a) has been widely studied and used in oxygen deficiency of the brain damage by adjusting the expression of the target genes to play the role of the protection of neurons.Phosphocreatine is the high-energy phosphate compound which is composed of phosphoric acid and creatine,and it is the temporarily stored form of high-energy phosphate. In the molecules of phosphocreatine, it has the nitrogen-phosphorus bonds which can release the high energy after hydrolyzation,consequently,the high energy conversion to the cells through the ADP-ATP pathway, not just can be an energy buffer, but can be used as a intracellular energy carrier. At present, as a high effective and low toxic myocardial protection medicine, exogenous creatine phosphate sodium (PCr) has be widely used in treating viral myocarditis, cardiac failure and so on,which has good curative effect, and as one of the additional constituent for cardioplegic solution in heart surgery,it has been collected by Martindale:The Extra Pharmacopoeia. In recent years studies have showed that PCr has the function of protection, restoration neurons, and can decrease the brain injury of newborns hypoxic-ischemic encephalopathy, cerebral infarction,and so on. But the corresponding animal laboratory data reports are less when influence some factors change, can PCr repair brain damage or inhibit brain cells degeneration or necrosis? The aim of this topic is that during the brain injury by anoxia, preliminarily study the change of NO and CaM content, the expression of HIF-1a by means of PCr intervention, and provided the support of laboratory for the clinical application of this drug.
Materials and methods
1Animals and groups
A total of75young rats were randomly divided into three groups, creatine phosphate sodium treated group (PCr group), normal saline model group (NS group) and normal control group,25for each group.The rats of PCr group and NS group were established anoxia model, the normal control group was not treated.
2drug application
The rats of PCr group were injected intraperitoneally with PCr on the0.5h before anoxia, and after anoxia immediate,24h,48h, by the dose of1.4mg/g, and in the same time, equal NS were injected respectively. Nothing was given the normal control group.
3Specimens Collection
On anoxia6h,each group took10young rats respectively which were taken in the brain and then were taken half of the brain tissue putting in the paraformaldehyde to make the pathological section; the other half of brain tissue was putted in the-80℃refrigerator to detect the relative content of HIF-la mRNA expression; on the last time of intraperitoneally injecting,each group took15young rats respectively which were taken in the brain and weighed, then putted in the-80℃refrigerator to detect the content of NO and CaM.
4Statistical analysis
To analyze all the data by SPSS17.0statistical software.Standard tolerance time used T test of independent sample. Comparison among groups of NO,CaM content and the relative content of HIF-1a expression used One-way ANOVA. LSD-^was used for multiple comparison. The difference was statistically significant when P <0.05.
Results
1Compared with NS group (7.15±0.90), the standard tolerance time of PCr group(7.97±0.75) prolonged significantly.
2Pathological changes:Compared with NS group, neural cell destruction of PCr group reduced, edema, necrosis eased significantly, and less of inflammatory cell was infiltrated.
3The NO content of PCr group[(0.73±0.13) umol/g] was a little bit higher (P<0.05) than that of normal control group[(0.55±0.07) umol/g],but lower (P<0.05) than that of NS group[(0.86±0.17) umol/g].
4The CaM content of PCr group[(41.19±1.13) ng/L] was a little bit higher (P<0.05) than normal control group[(39.56±0.86) ng/L], but lower (P<0.05) than model group[(42.04±0.76) ng/L].
5HIF-1a mRNA had hardly expression of normal control group (0.04±0.01), but the expression of NS group (1.09±0.01) increased, and PCr group (1.00±0.02) increased much more.
Conclusion
PCr may have neural protection by means of prolonging standard tolerance time, decreasing the CaM and NO content and increasing the expression of HIF-1a mRNA during brain injury by anoxia.
缺氧是由多种原因所致的循环血中氧分压或氧含量下降而导致组织细胞供氧不足的病理状态。而中枢神经系统是机体所有组织器官中对缺氧表现最为敏感的部位,易引起脑细胞水肿、变性、坏死,导致神经系统疾病,且脑损伤的严重程度与缺氧程度密切相关。而对于儿科常见缺氧性疾病如新生儿窒息(Asphyxia of newborn)、新生儿缺氧缺血性脑病(Hypoxic-ischemic encephalopathy, HIE)等,则易导致患儿惊厥、运动不协调或障碍、智力低下、学习记忆能力受损,严重者引起脑瘫甚至死亡,不仅对家庭和社会带来沉重的精神压力,也带来了难以负荷的经济负担。
能量代谢障碍是脑组织缺氧后最早发生的病理生理学改变,其后发生的一系列“瀑布样”反应,如氧自由基生成的增加,Ca2+大量内流等,相应引起一氧化氮(Nitric oxide, NO)及钙调蛋白(Calmodulin, CaM)含量的增加,导致神经细胞的变性坏死。而缺氧诱导因子-1a(Hypoxia-inducible factor-1alpha, HIF-1a)作为缺氧调节的重要因子,是目前研究比较广泛的在缺氧性脑损伤中通过调节多种靶基因的表达,从而发挥对神经元的保护作用。磷酸肌酸是由磷酸与肌酸组成的高能磷酸化合物,它是高能磷酸基的暂时贮存形式,其分子中存在氮-磷键,水解后可释放高能量,而且能够在高能量转换的细胞中通过ADP-ATP途径补充机体所需能量,因此既可作为一能量缓冲剂,又可以作为细胞内的能量载体。目前,外源性磷酸肌酸钠(Creatine Phosphate Sodium, PCr)作为一种高效低毒的心肌保护药,已经广泛应用于治疗病毒性心肌炎、心力衰竭等疾病,具有较好疗效,并且作为心脏手术中停搏液的附加成分之一,已被英国马丁代尔大药典收集；近年来有研究显示,PCr同时具有保护、修复神经元的作作,有临床资料显示,PCr可以减轻新生儿缺氧缺血性脑病、脑梗死等疾病的脑损伤程度,但是否通过影响某些因子的变化而发挥促进脑损伤修复或抑制脑细胞变性坏死的发生的相关动物实验室资料报导较少。本课题旨在从动物实验的角度初步探讨幼鼠缺氧后脑组织NO、CaM含量、HIF-1a mRNA的表达在磷酸肌酸钠干预下的变化,为该药的临床应用提供实验室支持。
材料和方法
1实验动物和分组
将75只SD幼鼠随机分为3组,磷酸肌酸钠治疗组(PCr组)25只,生理盐水模型组(NS组)25只,正常对照组25只,其中PCr组和NS组制作缺氧模型,正常对照组不作缺氧处理。
2药物应用
PCr组在幼鼠缺氧前0.5h、缺氧后即刻、24h及48h以1.4mg/g的剂量腹腔注射PCr, NS组在相同时间点腹腔注射等量的生理盐水。正常对照组不注射任何药物。
3标本采集
各组于缺氧后6h各取10只幼鼠,断头取脑,取一半脑组织置于多聚甲醛中固定24h,作病理切片备用；另一半脑组织置于-80℃冰箱中保存,作HIF-1amRNA表达的相对含量测定；各组于末次腹腔注射药物后各取15只幼鼠,断头取脑、称重,置于-80℃冰箱中保存,作NO、CaM含量测定。
4统计学分析
采用SPSS17.0进行分析。标准缺氧耐受时间采用独立样本T检验,NO、CaM含量及HIF-1a mRNA表达的相对含量的组间比较采用单因素方差分析(one-way ANOVA); LSD-t检验用于各组间的两两比较,以P<0.05为差异具有统计学意义。
结果
1与NS组(7.15±0.90)相比,PCr组(7.97±0.75)标准耐受时间明显延长,P<0.05。
2病理学改变：PCr组较NS组神经细胞破坏减少,水肿、坏死明显减轻,炎症细胞浸润较少。
3PCr组[(0.73±0.13)umol/g]的NO含量较正常对照组[(0.55±0.07)umol/g]稍高(P<0.05),但较NS组[(0.86±0.17)umol/g]有所降低(P<0.05)。
4PCr组[(41.19±1.13)ng/L]的CaM含量较正常对照组[(39.56±0.86)ng/L]稍高(P<0.05),但较NS组[(42.04±0.76)ng/L]有所降低(P<0.05)。
5正常对照组(0.04±0.01)几乎无HIF-1a mRNA表达,NS组(1.09±0.01)表达有所增加(P<0.01),PCr组(1.00±0.02)较NS组表达增加更为明显(P<0.05)。
结论
外源性PCr可以延长缺氧幼鼠标准缺氧耐受时间,明显减轻缺氧组幼鼠脑组织的病理学改变,显著降低缺氧组幼鼠NO、CaM含量,增加缺氧组幼鼠HIF-1amRNA的表达,从而发挥神经保护作用。
Background and objectives
Anoxia is the pathological state of low ventilation in tissue and cell,which is caused by the decrease of oxygen partial pressure or oxygen content in the circulation of blood by various reasons. In all organs of the body, the central nervous system is the most sensitive to the anoxia, which causes brain cells edema, degeneration and necrosis easily, even causes nerve systemic diseases.The common diseases in pediatric such as neonatal asphyxia of newborn and newborns hypoxic-ischemic encephalopathy (HIE) cause the children convulsions,the movement out of coordination or obstacles,hypophrenia and impaired ability of learning and memory, seriously cause cerebral palsy and even death. All that bring about heavy pressure and economic burden to the family and society.
Energy metabolization obstacle is the earliest pathological physiology change after anoxia in the brain,then produces a series of "waterfall" responses such as increase of the oxygen radical, excessive influx of calcium, and so on, corresponding causes increase of the nitric oxide(NO) and Calmodulin (CaM).These responses can cause degeneration and necrosis for nerve cells. As the important factor of oxygen adjustment, at present hypoxia-inducible factor1alpha (HIF-1a) has been widely studied and used in oxygen deficiency of the brain damage by adjusting the expression of the target genes to play the role of the protection of neurons.Phosphocreatine is the high-energy phosphate compound which is composed of phosphoric acid and creatine,and it is the temporarily stored form of high-energy phosphate. In the molecules of phosphocreatine, it has the nitrogen-phosphorus bonds which can release the high energy after hydrolyzation,consequently,the high energy conversion to the cells through the ADP-ATP pathway, not just can be an energy buffer, but can be used as a intracellular energy carrier. At present, as a high effective and low toxic myocardial protection medicine, exogenous creatine phosphate sodium (PCr) has be widely used in treating viral myocarditis, cardiac failure and so on,which has good curative effect, and as one of the additional constituent for cardioplegic solution in heart surgery,it has been collected by Martindale:The Extra Pharmacopoeia. In recent years studies have showed that PCr has the function of protection, restoration neurons, and can decrease the brain injury of newborns hypoxic-ischemic encephalopathy, cerebral infarction,and so on. But the corresponding animal laboratory data reports are less when influence some factors change, can PCr repair brain damage or inhibit brain cells degeneration or necrosis? The aim of this topic is that during the brain injury by anoxia, preliminarily study the change of NO and CaM content, the expression of HIF-1a by means of PCr intervention, and provided the support of laboratory for the clinical application of this drug.
Materials and methods
1Animals and groups
A total of75young rats were randomly divided into three groups, creatine phosphate sodium treated group (PCr group), normal saline model group (NS group) and normal control group,25for each group.The rats of PCr group and NS group were established anoxia model, the normal control group was not treated.
2drug application
The rats of PCr group were injected intraperitoneally with PCr on the0.5h before anoxia, and after anoxia immediate,24h,48h, by the dose of1.4mg/g, and in the same time, equal NS were injected respectively. Nothing was given the normal control group.
3Specimens Collection
On anoxia6h,each group took10young rats respectively which were taken in the brain and then were taken half of the brain tissue putting in the paraformaldehyde to make the pathological section; the other half of brain tissue was putted in the-80℃refrigerator to detect the relative content of HIF-la mRNA expression; on the last time of intraperitoneally injecting,each group took15young rats respectively which were taken in the brain and weighed, then putted in the-80℃refrigerator to detect the content of NO and CaM.
4Statistical analysis
To analyze all the data by SPSS17.0statistical software.Standard tolerance time used T test of independent sample. Comparison among groups of NO,CaM content and the relative content of HIF-1a expression used One-way ANOVA. LSD-^was used for multiple comparison. The difference was statistically significant when P <0.05.
Results
1Compared with NS group (7.15±0.90), the standard tolerance time of PCr group(7.97±0.75) prolonged significantly.
2Pathological changes:Compared with NS group, neural cell destruction of PCr group reduced, edema, necrosis eased significantly, and less of inflammatory cell was infiltrated.
3The NO content of PCr group[(0.73±0.13) umol/g] was a little bit higher (P<0.05) than that of normal control group[(0.55±0.07) umol/g],but lower (P<0.05) than that of NS group[(0.86±0.17) umol/g].
4The CaM content of PCr group[(41.19±1.13) ng/L] was a little bit higher (P<0.05) than normal control group[(39.56±0.86) ng/L], but lower (P<0.05) than model group[(42.04±0.76) ng/L].
5HIF-1a mRNA had hardly expression of normal control group (0.04±0.01), but the expression of NS group (1.09±0.01) increased, and PCr group (1.00±0.02) increased much more.
Conclusion
PCr may have neural protection by means of prolonging standard tolerance time, decreasing the CaM and NO content and increasing the expression of HIF-1a mRNA during brain injury by anoxia.
引文
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