白藜芦醇甙对缺氧缺血性脑损伤新生大鼠ERK通路的影响及其改善学习记忆能力的机制研究
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摘要
目的：缺氧缺血性脑损伤（hypoxic-ischemic brain damage，HIBD）是新生儿期危害最大的神经系统疾病之一，常引起新生儿死亡，存活者也存在不同程度的神经系统发育障碍。HIBD发病机制十分复杂，治疗主要采取综合性措施减轻症状，对脑细胞进行保护，尽量减轻脑组织的进一步损害。但是由于围产期脑细胞较成年期容易受损以及治疗窗口期的问题，导致这些治疗措施在新生儿仍需进一步探讨。而且对于成熟脑行之有效的治疗是否在未成熟脑也能够表现出显著的神经保护作用，以及各种治疗方法对于不断发育的脑组织是否具有持续保护作用，仍需更多的研究。值得注意的是，在受到损伤同时，机体还会产生相应的保护性因子对抗损伤反应，如何上调保护性因子水平且降低损伤性因子水平是临床治疗的重要靶点。
脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是突触可塑性和记忆的重要调节因子，在HIBD修复中起着重要的神经保护作用，而MAPK/ERK信号通路的激活可以反馈性抑制神经元的兴奋性毒性，起到神经保护作用，在各种细胞内信号激酶瀑布链中,细胞外信号调节激酶ERK是脑源性神经营养因子发挥保护作用最可能的细胞内机制。脑缺氧缺血后磷酸化ERK的高表达可能是内源性神经保护反应的结果。缺氧缺血脑损伤后，即刻早基因(Immediate-early Genes,IEGS)如c-Jun在短期内迅速表达，导致了一些后期效应基因被抑制或激活，最终神经细胞坏死、凋亡。因此采用药物维持保护性信号通路的激活，上调脑损伤保护性神经营养因子水平，同时下调引起早期神经损伤的因子如c-Jun的水平，是临床治疗缺氧缺血性脑损伤的重要思路。
已有的研究和我们的前期研究工作证明，中药单体白藜芦醇甙（Polydatin,PD）对心脑血管具有十分明显的保护作用，它具有调节血管张力，抑制血小板聚集，改善微循环，保护血管内皮、抗氧化等作用，并对脑缺氧缺血后急性期的大脑组织细胞损伤具有一定的保护作用。目前，应用PD治疗急性脑梗塞、帕金森病以及老年性痴呆均已取得很好的临床效果。这些基础研究和临床实践的结合为长期寻找一种有效治疗新生儿HIBD的潜力药物提供了新思路，更为重要的是它体现了整体调节效应的中药治疗疾病宗旨。但是迄今为止，有关PD对未成熟脑HIBD后远期学习记忆能力的影响及其作用机制的研究甚少。基于以上研究和理论基础，我们提出设想，将PD运用到新生大鼠HIBD的治疗，研究缺氧缺血性脑损伤对于新生大鼠远期学习记忆能力的影响，进一步探讨PD对于HIBD新生大鼠远期学习记忆能力的保护作用，从蛋白水平通过ERK通路以及神经保护性因子BDNF表达进一步探讨其对于HIBD新生大鼠学习记忆能力保护作用的可能机制，并从即刻早基因c-Jun表达进一步研究其神经保护机制，旨在进一步明确PD对HIBD的保护作用及机制，为PD在新生儿HIE中的临床应用提供实验基础和理论依据。
方法：
1.7日龄SD大鼠随机分为三组:假手术对照组（NS组），缺氧缺血组（HI组），PD干预组（PD组）。分离并结扎左侧颈总动脉2小时后吸入含氧8%的氮氧混合气体2小时参照Rice方法制备新生大鼠HIBD模型。NS组仅游离左颈总动脉但不结扎和行缺氧处理，PD组在缺氧缺血后每天腹腔注射0.1％PD10mg/kg10天，NS组和HI组注射等体积无菌生理盐水。缺氧缺血损伤后24小时、10天及21天三个时间HE染色光镜下观察各组大鼠皮层、海马区脑组织病理结构的变化。缺氧缺血损伤后21天采用Y-迷宫和跳台实验评估大鼠学习记忆功能的变化。
2.给予PD组新生大鼠0.1％PD10mg/kg干预治疗1天，NS组和HI组注射等体积无菌生理盐水1天，在缺氧缺血后24小时Western Blot方法检测各组大鼠左侧海马p-ERK，p-CREB表达的变化，免疫组化方法检测左侧皮层、海马CA1区、CA3区及DG区c-Jun表达的变化，Western Blot方法检测左侧海马c-Jun表达的变化。
3.给予PD组新生大鼠0.1％PD10mg/kg干预治疗10天，NS组和HI组注射等体积无菌生理盐水10天，免疫组化方法检测各组大鼠缺氧缺血后24小时、10天及21天三个时间点左侧皮层、海马CA1区、CA3区BDNF的表达变化。WesternBlot方法检测缺氧缺血后24小时、10天及21天三个时间点大鼠左侧海马BDNF的表达变化。
结果：
1. Y-迷宫实验结果显示,在第一天的学习测试和第二天的记忆保持测试中，同NS组比较，HI组全天总反应时间显著延长（P <0.01）、错误反应次数增加（P<0.01），主动回避率减少（P<0.01）。同HI组比较，PD组全天总反应时间显著减少（P<0.01）、错误反应次数减少（P<0.01），主动回避率增加（P<0.01）。
2.跳台实验结果显示,同NS组比较，在第一天学习测试中，HI组反应时间延长（P<0.01），错误次数增加（P<0.01），在第二天记忆保持测试中，HI组潜伏期缩短（P<0.01），错误次数增多（P<0.01）。同HI组比较，在第一天学习测试中，PD组反应时间短于HI组（P<0.05），错误次数少于HI组（P<0.01）,且错误次数与NS组比较无差异(P>0.05)。在第二天记忆保持测试中，PD组潜伏期长于HI组（P<0.05），错误次数少于HI组（P<0.01）,且错误次数与NS组比较无差异(P>0.05)。
3.缺氧缺血损伤后24小时，Western Blot结果显示NS组大鼠海马有p-ERK、p-CREB蛋白的基础表达，HI组大鼠海马p-ERK、p-CREB蛋白表达较NS组明显增高（P<0.01），PD组大鼠海马p-ERK、p-CREB蛋白表达同HI组相比明显增高（P<0.01）。
4.免疫组化结果显示，缺氧缺血损伤后24小时,HI组大鼠左侧皮层及海马CA1区、CA3区BDNF表达同NS组相比较明显增高（P<0.01）,10天仍高于NS组（P<0.01），随着损伤时间延长，HI组BDNF的表达逐渐回落,在21天HI组皮层及海马CA1区、CA3区BDNF表达同NS组相比无统计学差异（P>0.05）。PD组呈现出同样的趋势，缺氧缺血损伤后24小时,PD组左侧皮层及海马CA1区、CA3区BDNF表达同NS组相比较明显增高（P<0.01），皮层、海马CA1区与HI组相比较无统计学差异（P>0.05），CA3区BDNF的表达高于HI组（P<0.05），缺氧缺血损伤后10天PD组皮层及海马CA1区、CA3区BDNF的表达高于HI组（P<0.05），21天PD组皮层及海马CA1区、CA3区BDNF的表达高于HI组（P<0.05）。大鼠左侧海马BDNF Western Blot结果同免疫组化结果相近，缺氧缺血后，HI组及PD组海马BDNF表达同NS组相比增高，后随着时间延长逐渐回落，缺氧缺血损伤后21天HI组已降至NS组水平，PD组在24小时（P<0.05）、10天（P<0.01）及21天（P<0.05）BDNF表达高于HI组。
5.缺氧缺血损伤后24小时,HI组左侧皮层、海马CA1、CA3及DG区免疫组化结果可见c-Jun阳性表达明显高于NS组（P<0.01），PD组较HI组明显减少（P<0.01）。Western Blot显示HI组左侧海马c-Jun的表达HI组高于NS组（P<0.01），而PD组的表达低于HI组（P<0.01）。
6. HE染色结果显示光镜下NS组左侧大脑半球组织皮层、海马CA1区结构层次清晰，神经细胞形态、结构正常。缺氧缺血损伤后24小时、10天HI组左侧脑组织皮层变薄，海马锥体细胞层数减少，神经细胞排列紊乱，出现细胞肿胀、溶解，有明显神经元缺失、局灶性坏死。缺氧缺血损伤后21天皮层、海马等部位形成胶质瘢痕。PD组在各时间点仍有不同程度的神经细胞变性，但多数神经元结构较完整，海马锥体细胞层细胞形态、排列基本正常。
结论：
1. HIBD可以引起新生大鼠脑组织病理改变和学习记忆能力的下降，应用白藜芦醇甙干预可以减轻脑组织损伤，改善HIBD新生大鼠的学习记忆能力。
2.缺氧缺血性脑损伤后，新生大鼠大脑海马p-ERK及p-CREB表达增加，表明MAPK/ERK信号通路被激活，应用白藜芦醇甙干预能进一步增强海马p-ERK及p-CREB表达，提示白藜芦醇甙干预对于学习记忆的改善作用可能同其作用于MAPK/ERK信号通路有关。
3.缺氧缺血性脑损伤后，新生大鼠脑组织BDNF表达增加，应用白藜芦醇甙干预能进一步增强HIBD新生大鼠大脑皮层及海马BDNF的表达，并且延长其表达时间，这可能是白藜芦醇甙对于HIBD新生大鼠神经保护作用的机制之一。
4.缺氧缺血性脑损伤后，新生大鼠脑组织c-Jun表达增加，应用白藜芦醇甙干预降低HIBD新生大鼠大脑皮层、海马c-Jun的表达，可能对缺氧缺血后的神经元具有早期保护作用。
Objective: Hypoxic-ischemic brain damage（HIBD）in neonatal period is one ofthe most harmful diseases of the nervous system, which often causes the death ofneonates. The survival also has the varying degree of nervous system developmentaldisorders. HIBD pathogenesis is complicated. For the majority of neonatals, HIBDcomprehensive treatment alleviates the symptoms, protects brain tissue, and minimizesfurther injury of brain. But perinatal cells are easier to be damaged than in adulthood,which leads to further investigation of these therapeutic measures in the neonatals. Andwhether the effective treatment in the mature brain also take effect in the immaturebrain, whether various treatment methods has consistent protective effect for long-termcontinuous development still needs more research. Notably, during the brain damage,the body will produce corresponding protective factors against injury response.Therefore, studies of up-regulations of the protective factor level and reduction of injuryfactor level can lead to important targets in clinical treatment.
Brain derived neurotrophic factor is an important regulatory factor in synapticplasticity and memory, which plays a significant role in hypoxia-ischemia brain damagerepair as a neuro-protection. While in MAPK/ERK pathway activation, BDNF cancause feedback inhibition of the neuronal excitotoxicity and plays a neuro-protectiverole. In various intracellular signaling kinase cascade chains, extracellular signaling ofERK kinase is the most possible brain-derived neurotrophic intracellular mechanism inneuroprotection. After cerebral hypoxia-ischemia, the high expression ofphosphorylated ERK may be the results of endogenous neuroprotective responses. Afterhypoxia-ischemia brain damage, the immediate early genes such as c-Jun rapidly expresses in the short term, leading to some late effect genes inhibition or activation,and ultimately necrosis and apoptosis of nerve cells. Therefore the use of drugs tomaintain protective signaling pathway activation, up-regulation of the levels of braininjury protective neurotrophic factors, while reduction of early nerve injury caused byfactors such as c-Jun, is the important strategies of clinical treatment ofhypoxic-ischemic brain damage.
The existing research and our previous work demonstrated the traditional Chinesemedicine, monomer polydatin（PD）, has obvious protective effect in cardiovascular andcerebrovascular system. PD can function in the regulation of vascular tone, inhibition ofplatelet aggregation, improvement of microcirculation, protection of vascularendothelial cells and antioxidant effect. It also has the protective effect of cerebralhypoxia ischemia in acute period of brain tissue cell injury. Currently, PD achievedgood clinical results in clinical treatment of acute cerebral infarction, Parkinson'sdisease and senile dementia. These basic research and clinical practice provide a newthought to find an effective treatment for the potential drugs of neonatal HIBD. Moreimportantly, it reflects the aim of whole regulation in Chinese traditional medicinewithin the treatment of diseases. But so far, the study of the polydatin in long termlearning and memory ability of neonatal rat brains after cerebral hypoxia-ischemiainjury and its mechanism research is not well known. Based on the above research andtheoretical basis, we put forward a tentative idea about polydatin in which we appliedthe polydatin to the treatment of neonatal rat HIBD to study the effect ofhypoxic-ischemic brain damage in neonatal rats’ long term learning and memoryabilities. We further explored the possible mechanism of polydatin in HIBD neonatalrat’s long term learning and memory protection, protein levels of ERK pathway andnerve protection factor BDNF expression to clarify the mechanism of PD for HIBDneonatal rats’ learning and memory ability, and to detect the c-Jun expression to clarifythe neuroprotective mechanism of polydatin. These studies will further clarify theprotective role and mechanism of polydatin in cerebral hypoxic-ischemia injuryprotective effect, further provide the role of polydatin in clinical application andtheoretical basis of neonatal hypoxic-ischemic encephalopathy.
Methods:
1.7day old SD rats were randomly divided into three groups: false operationgroup (group NS), hypoxia and ischemia group (group HI), PD group (group PD).According to Rice’s methods for preparation of neonatal rat model of hypoxic-ischemic brain damage, separation and ligation of the left common carotid artery2hours afterinhalation of8%oxygen nitrogen oxygen gas mixture for2hour. In NS group, the ratswere only released left common carotid artery but were not ligated and gained anoxictreatment. In group PD, the hypoxia ischemia rats were intraperitoneal injected0.1%PD10mg/kg per day for10days. In group NS and group HI, the rats were injected theequal volume of sterile saline solution. After24hours,10days and21days hypoxiaischemia injury, the rat cortex, hippocampus brain tissue pathological structure changeswere observed by HE staining at the three times. After21days hypoxia ischemia injury,the rats were tested through Y maze and step-down test to evaluate the rats’ learningand memory function changes.
2. In PD group, inject hypoxic-ischemia neonatal rats0.1%PD10mg/kgintervention therapy for1day. In group NS and HI, inject the equal volume of sterilesaline solution for1day. Use western blot to detect the expression changes of p-ERKand p-CREB of rats after24hours hypoxic-ischemia treatment. Utilizeimmunohistochemical method to detect the c-Jun expression in hippocampal CA1, CA3and DG area. Use western blot to detect the expression of c-Jun in rats after24hoursHIBD.
3. In group PD, inject hypoxic-ischemia neonatal rats with0.1%PD10mg/kgintervention therapy for10days. In group NS and HI, inject the equal volume of sterilesaline solution for10days. Utilize immunohistochemical methods to detect the BDNFexpression in left cortical, hippocampal CA1and CA3area.
Results:
1. Y maze experimental results show that, in the first day of the learning test andthe next day of memory retention test, compared with the NS group, the total reactiontime in HI group was significantly prolonged (P <0.01), error number increased (P<0.01), active avoidance rate reduced (P <0.01). Compared with the HI group, the totalreaction time in PD group was significantly decreased (P <0.01), error numberdecreased (P <0.01), active avoidance rate increased (P <0.01).
2. The experimental results of Step-down test show that, compared with the NSgroup, in the first day learning test, in HI group, reaction time extended (P <0.01), thenumber of errors increased (P <0.01), in the next day memory retention test, in HIgroup, latency reduced (P <0.01), the number of errors increased (P <0.01).Compared with the HI group, in the first day learning test, in PD group, reaction timereduced more than in HI group (P <0.05), the number of errors was less than in HI group (P <0.01), and the number of errors compared with NS group had nodifferences (P>0.05).in the next day memory retention test, in PD group, latency islonger than in HI group (P <0.05), the number of errors in less than in HI group (P <0.01), and the number of errors compared with NS group had no differences (P>0.05).
3. After24hours hypoxic-ischemia injury, the western blot results showed that rathippocampal areas in NS group had the basal expression of p-ERK, p-CREB. In HIgroup, the p-ERK, p-CREB expression in rat hippocampal area were increased whencompared with NS group (P <0.01), In PD group, rat hippocampal p-ERK, p-CREBexpression were significantly increased when compared with HI group (P <0.01).
4. Immunohistochemical results showed that, after24hours hypoxic-ischemiainjury, the BDNF expression of HI rats compared with the NS group significantlyincreased in cortex contralateral hippocampal CA1and CA3area (P <0.01). After10days, it is still higher than that of group NS (P <0.01), with the prolongation of injurytime, the BDNF expression in HI group gradually fall, on the21day, there are nosignificantly different BDNF expression in HI group cortex and hippocampal CA1area,CA3area when compared with NS group (P>0.05). The PD group showed the sametrend, after24hours hypoxic-ischemia injury, the BDNF expression of PD groupsignificantly increased in cortex contralateral hippocampal CA1area, CA3areacompared with the NS group (P <0.01), while in cortical, hippocampal CA1area, therewere no significant difference (P>0.05). The expression of BDNF in CA3area ishigher than that of HI group (P <0.05). The BDNF expression in CA3area is higherthan that of HI group (P <0.05), on the21day, the BDNF expression in PD group washigher than that of group HI (P <0.05). In rats with hypoxic-ischemic hippocampal area,western blot data gain the similar results with the immunohistochemical data, afterhypoxic-ischemia, BDNF expression in HI group and PD group were increased whencompared with NS group, with the prolongation of time, the expression of BDNFgradually fall. After21days hypoxic-ischemia injury in HI group, it had fallen to thelevel of NS group, in PD group, at24hours (P <0.05),10days (P <0.01) and21days(P <0.05), BDNF expression is higher than that of HI group.
5. After24hours hypoxic-ischemia injury, in HI group, in left cortex,hippocampal CA1, CA3and DG area, the immunohistochemical results showed thepositive expression of c-Jun was significantly higher than that of group NS (P <0.01),in PD group, it was significantly decreased (P <0.01). The western blot results showed that the c-Jun expression in left hippocampal in HI group was higher than that of groupNS (P <0.01), while in PD group, its expression was lower than that in the HI group (P<0.01).
6. Under a light microscope, HE staining showed that the left hemisphere of thebrain organization of cortical, hippocampal CA1area in NS group displayed clear layers,normal nerve cell structure and morphology. After24hours hypoxic-ischemia injury in10days HI group, left brain tissue became thin, hippocampal pyramidal cell layerreduces, nerve cell deranged, cell swelled, dissoluted, and displayed the obviousneuronal loss and focal necrosis. After21days hypoxic-ischemia injury, cortex,hippocampus and other areas formed the glial scar. The rats in PD group at each timepoint still have various degrees of neuronal degeneration, but the majority of theneurons structure are complete, and the hippocampal pyramidal cell layer, cell shapeand arrangement are generally normal.
Conclusion:
1. HIBD can cause brain tissue pathological changes. The learning and memoryability of neonatal rats were reduced. Polydatin treatment can alleviate the injury ofbrain tissue of HIBD rats and improve the ability of learning and memory.
2. After hypoxic-ischemic brain damage, the expression of p-ERK and p-CREBwere increased in hippocampal areas of neonatal rats, MAPK/ERK signaling pathwayis activated. Polydatin can enhance hippocampal p-ERK and p-CREB expression, whichsuggested that the learning memory protection of polydatin may be mediated by MAPK/ERK signal pathway.
3. The expression of BDNF in HIBD neonatal rats is increased afterhypoxic-ischemia injury. Polydatin can up-regulate and last the expression of HIBD inbrain tissue of neonatal rats in cerebral cortex and hippocampus. This effect may beinvolved in hypoxic-ischemia neuroprotection.
4. The expression of c-Jun is increased after hypoxic-ischemia injury. Polydatinreduces c-Jun expression in HIBD neonatal rats’ cerebral cortex, hippocampus, whichmay have an early protective effect in neurons after hypoxic-ischemia.
脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是突触可塑性和记忆的重要调节因子，在HIBD修复中起着重要的神经保护作用，而MAPK/ERK信号通路的激活可以反馈性抑制神经元的兴奋性毒性，起到神经保护作用，在各种细胞内信号激酶瀑布链中,细胞外信号调节激酶ERK是脑源性神经营养因子发挥保护作用最可能的细胞内机制。脑缺氧缺血后磷酸化ERK的高表达可能是内源性神经保护反应的结果。缺氧缺血脑损伤后，即刻早基因(Immediate-early Genes,IEGS)如c-Jun在短期内迅速表达，导致了一些后期效应基因被抑制或激活，最终神经细胞坏死、凋亡。因此采用药物维持保护性信号通路的激活，上调脑损伤保护性神经营养因子水平，同时下调引起早期神经损伤的因子如c-Jun的水平，是临床治疗缺氧缺血性脑损伤的重要思路。
已有的研究和我们的前期研究工作证明，中药单体白藜芦醇甙（Polydatin,PD）对心脑血管具有十分明显的保护作用，它具有调节血管张力，抑制血小板聚集，改善微循环，保护血管内皮、抗氧化等作用，并对脑缺氧缺血后急性期的大脑组织细胞损伤具有一定的保护作用。目前，应用PD治疗急性脑梗塞、帕金森病以及老年性痴呆均已取得很好的临床效果。这些基础研究和临床实践的结合为长期寻找一种有效治疗新生儿HIBD的潜力药物提供了新思路，更为重要的是它体现了整体调节效应的中药治疗疾病宗旨。但是迄今为止，有关PD对未成熟脑HIBD后远期学习记忆能力的影响及其作用机制的研究甚少。基于以上研究和理论基础，我们提出设想，将PD运用到新生大鼠HIBD的治疗，研究缺氧缺血性脑损伤对于新生大鼠远期学习记忆能力的影响，进一步探讨PD对于HIBD新生大鼠远期学习记忆能力的保护作用，从蛋白水平通过ERK通路以及神经保护性因子BDNF表达进一步探讨其对于HIBD新生大鼠学习记忆能力保护作用的可能机制，并从即刻早基因c-Jun表达进一步研究其神经保护机制，旨在进一步明确PD对HIBD的保护作用及机制，为PD在新生儿HIE中的临床应用提供实验基础和理论依据。
方法：
1.7日龄SD大鼠随机分为三组:假手术对照组（NS组），缺氧缺血组（HI组），PD干预组（PD组）。分离并结扎左侧颈总动脉2小时后吸入含氧8%的氮氧混合气体2小时参照Rice方法制备新生大鼠HIBD模型。NS组仅游离左颈总动脉但不结扎和行缺氧处理，PD组在缺氧缺血后每天腹腔注射0.1％PD10mg/kg10天，NS组和HI组注射等体积无菌生理盐水。缺氧缺血损伤后24小时、10天及21天三个时间HE染色光镜下观察各组大鼠皮层、海马区脑组织病理结构的变化。缺氧缺血损伤后21天采用Y-迷宫和跳台实验评估大鼠学习记忆功能的变化。
2.给予PD组新生大鼠0.1％PD10mg/kg干预治疗1天，NS组和HI组注射等体积无菌生理盐水1天，在缺氧缺血后24小时Western Blot方法检测各组大鼠左侧海马p-ERK，p-CREB表达的变化，免疫组化方法检测左侧皮层、海马CA1区、CA3区及DG区c-Jun表达的变化，Western Blot方法检测左侧海马c-Jun表达的变化。
3.给予PD组新生大鼠0.1％PD10mg/kg干预治疗10天，NS组和HI组注射等体积无菌生理盐水10天，免疫组化方法检测各组大鼠缺氧缺血后24小时、10天及21天三个时间点左侧皮层、海马CA1区、CA3区BDNF的表达变化。WesternBlot方法检测缺氧缺血后24小时、10天及21天三个时间点大鼠左侧海马BDNF的表达变化。
结果：
1. Y-迷宫实验结果显示,在第一天的学习测试和第二天的记忆保持测试中，同NS组比较，HI组全天总反应时间显著延长（P <0.01）、错误反应次数增加（P<0.01），主动回避率减少（P<0.01）。同HI组比较，PD组全天总反应时间显著减少（P<0.01）、错误反应次数减少（P<0.01），主动回避率增加（P<0.01）。
2.跳台实验结果显示,同NS组比较，在第一天学习测试中，HI组反应时间延长（P<0.01），错误次数增加（P<0.01），在第二天记忆保持测试中，HI组潜伏期缩短（P<0.01），错误次数增多（P<0.01）。同HI组比较，在第一天学习测试中，PD组反应时间短于HI组（P<0.05），错误次数少于HI组（P<0.01）,且错误次数与NS组比较无差异(P>0.05)。在第二天记忆保持测试中，PD组潜伏期长于HI组（P<0.05），错误次数少于HI组（P<0.01）,且错误次数与NS组比较无差异(P>0.05)。
3.缺氧缺血损伤后24小时，Western Blot结果显示NS组大鼠海马有p-ERK、p-CREB蛋白的基础表达，HI组大鼠海马p-ERK、p-CREB蛋白表达较NS组明显增高（P<0.01），PD组大鼠海马p-ERK、p-CREB蛋白表达同HI组相比明显增高（P<0.01）。
4.免疫组化结果显示，缺氧缺血损伤后24小时,HI组大鼠左侧皮层及海马CA1区、CA3区BDNF表达同NS组相比较明显增高（P<0.01）,10天仍高于NS组（P<0.01），随着损伤时间延长，HI组BDNF的表达逐渐回落,在21天HI组皮层及海马CA1区、CA3区BDNF表达同NS组相比无统计学差异（P>0.05）。PD组呈现出同样的趋势，缺氧缺血损伤后24小时,PD组左侧皮层及海马CA1区、CA3区BDNF表达同NS组相比较明显增高（P<0.01），皮层、海马CA1区与HI组相比较无统计学差异（P>0.05），CA3区BDNF的表达高于HI组（P<0.05），缺氧缺血损伤后10天PD组皮层及海马CA1区、CA3区BDNF的表达高于HI组（P<0.05），21天PD组皮层及海马CA1区、CA3区BDNF的表达高于HI组（P<0.05）。大鼠左侧海马BDNF Western Blot结果同免疫组化结果相近，缺氧缺血后，HI组及PD组海马BDNF表达同NS组相比增高，后随着时间延长逐渐回落，缺氧缺血损伤后21天HI组已降至NS组水平，PD组在24小时（P<0.05）、10天（P<0.01）及21天（P<0.05）BDNF表达高于HI组。
5.缺氧缺血损伤后24小时,HI组左侧皮层、海马CA1、CA3及DG区免疫组化结果可见c-Jun阳性表达明显高于NS组（P<0.01），PD组较HI组明显减少（P<0.01）。Western Blot显示HI组左侧海马c-Jun的表达HI组高于NS组（P<0.01），而PD组的表达低于HI组（P<0.01）。
6. HE染色结果显示光镜下NS组左侧大脑半球组织皮层、海马CA1区结构层次清晰，神经细胞形态、结构正常。缺氧缺血损伤后24小时、10天HI组左侧脑组织皮层变薄，海马锥体细胞层数减少，神经细胞排列紊乱，出现细胞肿胀、溶解，有明显神经元缺失、局灶性坏死。缺氧缺血损伤后21天皮层、海马等部位形成胶质瘢痕。PD组在各时间点仍有不同程度的神经细胞变性，但多数神经元结构较完整，海马锥体细胞层细胞形态、排列基本正常。
结论：
1. HIBD可以引起新生大鼠脑组织病理改变和学习记忆能力的下降，应用白藜芦醇甙干预可以减轻脑组织损伤，改善HIBD新生大鼠的学习记忆能力。
2.缺氧缺血性脑损伤后，新生大鼠大脑海马p-ERK及p-CREB表达增加，表明MAPK/ERK信号通路被激活，应用白藜芦醇甙干预能进一步增强海马p-ERK及p-CREB表达，提示白藜芦醇甙干预对于学习记忆的改善作用可能同其作用于MAPK/ERK信号通路有关。
3.缺氧缺血性脑损伤后，新生大鼠脑组织BDNF表达增加，应用白藜芦醇甙干预能进一步增强HIBD新生大鼠大脑皮层及海马BDNF的表达，并且延长其表达时间，这可能是白藜芦醇甙对于HIBD新生大鼠神经保护作用的机制之一。
4.缺氧缺血性脑损伤后，新生大鼠脑组织c-Jun表达增加，应用白藜芦醇甙干预降低HIBD新生大鼠大脑皮层、海马c-Jun的表达，可能对缺氧缺血后的神经元具有早期保护作用。
Objective: Hypoxic-ischemic brain damage（HIBD）in neonatal period is one ofthe most harmful diseases of the nervous system, which often causes the death ofneonates. The survival also has the varying degree of nervous system developmentaldisorders. HIBD pathogenesis is complicated. For the majority of neonatals, HIBDcomprehensive treatment alleviates the symptoms, protects brain tissue, and minimizesfurther injury of brain. But perinatal cells are easier to be damaged than in adulthood,which leads to further investigation of these therapeutic measures in the neonatals. Andwhether the effective treatment in the mature brain also take effect in the immaturebrain, whether various treatment methods has consistent protective effect for long-termcontinuous development still needs more research. Notably, during the brain damage,the body will produce corresponding protective factors against injury response.Therefore, studies of up-regulations of the protective factor level and reduction of injuryfactor level can lead to important targets in clinical treatment.
Brain derived neurotrophic factor is an important regulatory factor in synapticplasticity and memory, which plays a significant role in hypoxia-ischemia brain damagerepair as a neuro-protection. While in MAPK/ERK pathway activation, BDNF cancause feedback inhibition of the neuronal excitotoxicity and plays a neuro-protectiverole. In various intracellular signaling kinase cascade chains, extracellular signaling ofERK kinase is the most possible brain-derived neurotrophic intracellular mechanism inneuroprotection. After cerebral hypoxia-ischemia, the high expression ofphosphorylated ERK may be the results of endogenous neuroprotective responses. Afterhypoxia-ischemia brain damage, the immediate early genes such as c-Jun rapidly expresses in the short term, leading to some late effect genes inhibition or activation,and ultimately necrosis and apoptosis of nerve cells. Therefore the use of drugs tomaintain protective signaling pathway activation, up-regulation of the levels of braininjury protective neurotrophic factors, while reduction of early nerve injury caused byfactors such as c-Jun, is the important strategies of clinical treatment ofhypoxic-ischemic brain damage.
The existing research and our previous work demonstrated the traditional Chinesemedicine, monomer polydatin（PD）, has obvious protective effect in cardiovascular andcerebrovascular system. PD can function in the regulation of vascular tone, inhibition ofplatelet aggregation, improvement of microcirculation, protection of vascularendothelial cells and antioxidant effect. It also has the protective effect of cerebralhypoxia ischemia in acute period of brain tissue cell injury. Currently, PD achievedgood clinical results in clinical treatment of acute cerebral infarction, Parkinson'sdisease and senile dementia. These basic research and clinical practice provide a newthought to find an effective treatment for the potential drugs of neonatal HIBD. Moreimportantly, it reflects the aim of whole regulation in Chinese traditional medicinewithin the treatment of diseases. But so far, the study of the polydatin in long termlearning and memory ability of neonatal rat brains after cerebral hypoxia-ischemiainjury and its mechanism research is not well known. Based on the above research andtheoretical basis, we put forward a tentative idea about polydatin in which we appliedthe polydatin to the treatment of neonatal rat HIBD to study the effect ofhypoxic-ischemic brain damage in neonatal rats’ long term learning and memoryabilities. We further explored the possible mechanism of polydatin in HIBD neonatalrat’s long term learning and memory protection, protein levels of ERK pathway andnerve protection factor BDNF expression to clarify the mechanism of PD for HIBDneonatal rats’ learning and memory ability, and to detect the c-Jun expression to clarifythe neuroprotective mechanism of polydatin. These studies will further clarify theprotective role and mechanism of polydatin in cerebral hypoxic-ischemia injuryprotective effect, further provide the role of polydatin in clinical application andtheoretical basis of neonatal hypoxic-ischemic encephalopathy.
Methods:
1.7day old SD rats were randomly divided into three groups: false operationgroup (group NS), hypoxia and ischemia group (group HI), PD group (group PD).According to Rice’s methods for preparation of neonatal rat model of hypoxic-ischemic brain damage, separation and ligation of the left common carotid artery2hours afterinhalation of8%oxygen nitrogen oxygen gas mixture for2hour. In NS group, the ratswere only released left common carotid artery but were not ligated and gained anoxictreatment. In group PD, the hypoxia ischemia rats were intraperitoneal injected0.1%PD10mg/kg per day for10days. In group NS and group HI, the rats were injected theequal volume of sterile saline solution. After24hours,10days and21days hypoxiaischemia injury, the rat cortex, hippocampus brain tissue pathological structure changeswere observed by HE staining at the three times. After21days hypoxia ischemia injury,the rats were tested through Y maze and step-down test to evaluate the rats’ learningand memory function changes.
2. In PD group, inject hypoxic-ischemia neonatal rats0.1%PD10mg/kgintervention therapy for1day. In group NS and HI, inject the equal volume of sterilesaline solution for1day. Use western blot to detect the expression changes of p-ERKand p-CREB of rats after24hours hypoxic-ischemia treatment. Utilizeimmunohistochemical method to detect the c-Jun expression in hippocampal CA1, CA3and DG area. Use western blot to detect the expression of c-Jun in rats after24hoursHIBD.
3. In group PD, inject hypoxic-ischemia neonatal rats with0.1%PD10mg/kgintervention therapy for10days. In group NS and HI, inject the equal volume of sterilesaline solution for10days. Utilize immunohistochemical methods to detect the BDNFexpression in left cortical, hippocampal CA1and CA3area.
Results:
1. Y maze experimental results show that, in the first day of the learning test andthe next day of memory retention test, compared with the NS group, the total reactiontime in HI group was significantly prolonged (P <0.01), error number increased (P<0.01), active avoidance rate reduced (P <0.01). Compared with the HI group, the totalreaction time in PD group was significantly decreased (P <0.01), error numberdecreased (P <0.01), active avoidance rate increased (P <0.01).
2. The experimental results of Step-down test show that, compared with the NSgroup, in the first day learning test, in HI group, reaction time extended (P <0.01), thenumber of errors increased (P <0.01), in the next day memory retention test, in HIgroup, latency reduced (P <0.01), the number of errors increased (P <0.01).Compared with the HI group, in the first day learning test, in PD group, reaction timereduced more than in HI group (P <0.05), the number of errors was less than in HI group (P <0.01), and the number of errors compared with NS group had nodifferences (P>0.05).in the next day memory retention test, in PD group, latency islonger than in HI group (P <0.05), the number of errors in less than in HI group (P <0.01), and the number of errors compared with NS group had no differences (P>0.05).
3. After24hours hypoxic-ischemia injury, the western blot results showed that rathippocampal areas in NS group had the basal expression of p-ERK, p-CREB. In HIgroup, the p-ERK, p-CREB expression in rat hippocampal area were increased whencompared with NS group (P <0.01), In PD group, rat hippocampal p-ERK, p-CREBexpression were significantly increased when compared with HI group (P <0.01).
4. Immunohistochemical results showed that, after24hours hypoxic-ischemiainjury, the BDNF expression of HI rats compared with the NS group significantlyincreased in cortex contralateral hippocampal CA1and CA3area (P <0.01). After10days, it is still higher than that of group NS (P <0.01), with the prolongation of injurytime, the BDNF expression in HI group gradually fall, on the21day, there are nosignificantly different BDNF expression in HI group cortex and hippocampal CA1area,CA3area when compared with NS group (P>0.05). The PD group showed the sametrend, after24hours hypoxic-ischemia injury, the BDNF expression of PD groupsignificantly increased in cortex contralateral hippocampal CA1area, CA3areacompared with the NS group (P <0.01), while in cortical, hippocampal CA1area, therewere no significant difference (P>0.05). The expression of BDNF in CA3area ishigher than that of HI group (P <0.05). The BDNF expression in CA3area is higherthan that of HI group (P <0.05), on the21day, the BDNF expression in PD group washigher than that of group HI (P <0.05). In rats with hypoxic-ischemic hippocampal area,western blot data gain the similar results with the immunohistochemical data, afterhypoxic-ischemia, BDNF expression in HI group and PD group were increased whencompared with NS group, with the prolongation of time, the expression of BDNFgradually fall. After21days hypoxic-ischemia injury in HI group, it had fallen to thelevel of NS group, in PD group, at24hours (P <0.05),10days (P <0.01) and21days(P <0.05), BDNF expression is higher than that of HI group.
5. After24hours hypoxic-ischemia injury, in HI group, in left cortex,hippocampal CA1, CA3and DG area, the immunohistochemical results showed thepositive expression of c-Jun was significantly higher than that of group NS (P <0.01),in PD group, it was significantly decreased (P <0.01). The western blot results showed that the c-Jun expression in left hippocampal in HI group was higher than that of groupNS (P <0.01), while in PD group, its expression was lower than that in the HI group (P<0.01).
6. Under a light microscope, HE staining showed that the left hemisphere of thebrain organization of cortical, hippocampal CA1area in NS group displayed clear layers,normal nerve cell structure and morphology. After24hours hypoxic-ischemia injury in10days HI group, left brain tissue became thin, hippocampal pyramidal cell layerreduces, nerve cell deranged, cell swelled, dissoluted, and displayed the obviousneuronal loss and focal necrosis. After21days hypoxic-ischemia injury, cortex,hippocampus and other areas formed the glial scar. The rats in PD group at each timepoint still have various degrees of neuronal degeneration, but the majority of theneurons structure are complete, and the hippocampal pyramidal cell layer, cell shapeand arrangement are generally normal.
Conclusion:
1. HIBD can cause brain tissue pathological changes. The learning and memoryability of neonatal rats were reduced. Polydatin treatment can alleviate the injury ofbrain tissue of HIBD rats and improve the ability of learning and memory.
2. After hypoxic-ischemic brain damage, the expression of p-ERK and p-CREBwere increased in hippocampal areas of neonatal rats, MAPK/ERK signaling pathwayis activated. Polydatin can enhance hippocampal p-ERK and p-CREB expression, whichsuggested that the learning memory protection of polydatin may be mediated by MAPK/ERK signal pathway.
3. The expression of BDNF in HIBD neonatal rats is increased afterhypoxic-ischemia injury. Polydatin can up-regulate and last the expression of HIBD inbrain tissue of neonatal rats in cerebral cortex and hippocampus. This effect may beinvolved in hypoxic-ischemia neuroprotection.
4. The expression of c-Jun is increased after hypoxic-ischemia injury. Polydatinreduces c-Jun expression in HIBD neonatal rats’ cerebral cortex, hippocampus, whichmay have an early protective effect in neurons after hypoxic-ischemia.
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