早产儿脑白质损伤动物模型的建立及早期干预的疗效研究
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摘要
目的:
建立4日龄SD大鼠脑白质损伤(white matter damage,WMD)动物模型,早期分别给予重组人红细胞生成素(recombinant human erythropoietin,rHuEPO)、单唾液酸四己糖神经节苷脂(monosialotetrahexosylganglioside, GM1)或神经生长因子(nerve growth factor,NGF)治疗,比较干预后大鼠的病理形态学和神经行为功能改变情况,探讨rHuEPO、GM1和NGF对缺血缺氧性WMD新生大鼠的神经保护作用,为临床早期干预早产儿脑白质损伤提供依据。
方法:
4日龄SD大鼠290只,随机分为5组:假手术组、生理盐水(saline, NS)组、EPO组、GM1组和NGF组。假手术组仅切开颈部皮肤,分离双侧颈总动脉,再缝合颈部伤口,其余四组结扎双侧颈总动脉,再分别予以等体积的NS 0.01 ml/g、EPO 5 IU/g、GM1 0.02 mg/g、NGF 2 IU/g腹腔内注射,GM1和NGF间隔24h重复给药,共给药5次。各组动物分别于术后(假手术组于对应时间)24h、48h、72h、7d、26d称量体重,再断头处死。常规H-E染色观察脑白质损害情况,免疫组织化学染色观察各时间点髓鞘碱性蛋白(myelin basic protein,MBP)、β淀粉样前体蛋白(β-amyloid precursor protein,β-APP)和胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)抗原的表达。术后26d(生后30d)采用悬吊、斜坡和旷场试验进行神经行为学检测。
结果:
1.四组WMD大鼠体重明显增长不良,各时间点NS组、EPO组、GM1组和NGF组大鼠的体重均与假手术组有显著性差异(P<0.05);而术后7d、26d EPO组大鼠和术后26d NGF组体重高于NS组,差异有显著性意义(P<0.05);各时间点GM1组大鼠体重均与NS组无显著性差异(P>0.05)。
2.缺血缺氧后大鼠出现脑室周围白质损伤,光镜下表现为脑室周围白质细胞肿胀、坏死和凋亡、组织疏松、侧脑室进行性扩大。与NS组比较,EPO组、GM1组和NGF组大鼠光镜下病理变化无明显差异,但术后72h片状坏死的范围较小,术后7d、26d侧脑室扩大的程度较轻。
3.缺氧缺血后大鼠脑组织免疫组化染色MBP阳性细胞百分率降低,APP、GFAP阳性细胞百分率增高。给予rHuEPO、GM1、NGF治疗后,术后72h、7d MBP阳性细胞百分率较NS组增高,术后72h、7d、26d APP阳性细胞百分率较NS组降低,术后48h、72h、7d、26d GFAP阳性细胞百分率较NS组降低,差异有显著性意义(P<0.05)。
4.30日龄时, NS组、EPO组、GM1组和NGF组大鼠反应迟钝、自主活动减少,灵活性、稳定性降低。NS组大鼠悬吊、斜坡和旷场试验的结果均差于假手术组,差异有显著性意义(P<0.05);EPO组、GM1组和NGF组大鼠悬吊、斜坡和旷场试验的结果均优于NS组,差异有显著性意义(P<0.05)。
结论:
采用4日龄SD大鼠双侧颈总动脉结扎术可成功建立早产儿脑白质损伤动物模型;早期给予EPO、GM1或NGF干预治疗能够促进大鼠的体格生长和脑白质损伤的修复,改善其神经行为功能。
Objective:
To establish a 4-day-old SD rat animal model of white matter damage, and observe the changes of pathological morphology and neurobehavioral function of the newborn rats after given early treatment with recombinant human erythropoietin (rHuEPO), monosialotetrahexosylganglioside (GM1), or nerve growth factor (NGF). To discuss the neural protect effects of rHuEPO, GM1 and NGF on newborn rats with ischemia-hypoxia white matter damage, and provide evidence of early treatment on preterm infants.
Methods:
Totally 290 4-day-old SD rats were randomly divided into 5 groups: sham-operated group, saline (NS) group, EPO group, GM1 group and NGF group. The sham-operated group were only cut open the neck skin and separated the bilateral carotid arteries without occlusion; and the other four groups were subjected to bilateral carotid artery occlusion (BCAO), after that were separately intraperitoneally injected NS 0.01 ml/g, EPO 5 IU/g, GM1 0.02 mg/g, NGF 2 IU/g; GM1 and NGF were repeatedly injected every 24h, totally given 5 doses. The rats were separately killed at 24h, 48h, 72h, 7d and 26d post-operation. After routine H-E dyeing, light microscopy was used to observe brain pathological changes. Immunohistochemistry methods were used to detect the expression of myelin basic protein (MBP),β-amyloid precursor protein (β-APP) and glial fibrillary acidic protein (GFAP) at each observing time-point post-operation. Hanging test, inclined plane test and open field test were performed on the rats 26 days post-operation.
Results:
1. Weight of four groups of WMD rats were significantly grown slowly. The weight of NS group, EPO group, GM1 group and NGF group were significantly lower than sham-operated group at each observing time-point post-operation (P<0.05). But the weight of EPO group was significantly higher than that of NS group at 7d and 26d post-operation, and the weight of NGF group was significantly higher than that of NS group at 26d post-operation(P<0.05).The weight of GM1 group had no significant difference compared with NS group at each observing time-point post-operation(P>0.05).
2. After ischemia-hypoxia, light microscopy showed periventricular white matter damage, included cell swollen, necrosis and apoptosis, tissue loose and lateral ventricle enlarging. Under light microscopy, the pathological changes of EPO group, GM1 group and NGF group had no obvious differences between them; but when compared with NS group, the range of necrosis was smaller at 72h post-operation, and the extent of lateral ventricle enlarging was smaller at 7d and 26d post-operation.
3. After ischemia-hypoxia, the immunohistochemistry dyeing showed that the percentage of MBP positive cells was decreased, andβ- APP, GFAP positive cells percentages were increased. After treated with rHuEPO, GM1, NGF, the percentage of MBP positive cells increased significantly than that of NS group at 72h or 7d post-operation; APP positive cells percentage decreased significantly than that of NS group at 72h, 7d or 26d post-operation; GFAP positive cells percentage decreased significantly than that of NS group at 48h, 72h, 7d or 26d post-operation(P<0.05).
4. When 30-day-old, the NS group, EPO group, GM1 group and NGF group rats responsed stolidly, their autonomic acivities reduced, flexibility and stability decreased. The results of hanging test, inclined plane test and open field test of NS group were significantly worse than those of sham-operated group(P<0.05). The results of hanging test, inclined plane test and open field test of EPO group, GM1 group and NGF group were significantly better than those of NS group. (P<0.05)
Conclusion:
Using 4-day-old SD rat with BCAO, an animal model of white matter damage can be successfully set up. Early treatment with rHuEPO, GM1 or NGF can improve the rat’s growth and repair of WMD, and ameliorate the rat’s neurobehavioral function.
建立4日龄SD大鼠脑白质损伤(white matter damage,WMD)动物模型,早期分别给予重组人红细胞生成素(recombinant human erythropoietin,rHuEPO)、单唾液酸四己糖神经节苷脂(monosialotetrahexosylganglioside, GM1)或神经生长因子(nerve growth factor,NGF)治疗,比较干预后大鼠的病理形态学和神经行为功能改变情况,探讨rHuEPO、GM1和NGF对缺血缺氧性WMD新生大鼠的神经保护作用,为临床早期干预早产儿脑白质损伤提供依据。
方法:
4日龄SD大鼠290只,随机分为5组:假手术组、生理盐水(saline, NS)组、EPO组、GM1组和NGF组。假手术组仅切开颈部皮肤,分离双侧颈总动脉,再缝合颈部伤口,其余四组结扎双侧颈总动脉,再分别予以等体积的NS 0.01 ml/g、EPO 5 IU/g、GM1 0.02 mg/g、NGF 2 IU/g腹腔内注射,GM1和NGF间隔24h重复给药,共给药5次。各组动物分别于术后(假手术组于对应时间)24h、48h、72h、7d、26d称量体重,再断头处死。常规H-E染色观察脑白质损害情况,免疫组织化学染色观察各时间点髓鞘碱性蛋白(myelin basic protein,MBP)、β淀粉样前体蛋白(β-amyloid precursor protein,β-APP)和胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)抗原的表达。术后26d(生后30d)采用悬吊、斜坡和旷场试验进行神经行为学检测。
结果:
1.四组WMD大鼠体重明显增长不良,各时间点NS组、EPO组、GM1组和NGF组大鼠的体重均与假手术组有显著性差异(P<0.05);而术后7d、26d EPO组大鼠和术后26d NGF组体重高于NS组,差异有显著性意义(P<0.05);各时间点GM1组大鼠体重均与NS组无显著性差异(P>0.05)。
2.缺血缺氧后大鼠出现脑室周围白质损伤,光镜下表现为脑室周围白质细胞肿胀、坏死和凋亡、组织疏松、侧脑室进行性扩大。与NS组比较,EPO组、GM1组和NGF组大鼠光镜下病理变化无明显差异,但术后72h片状坏死的范围较小,术后7d、26d侧脑室扩大的程度较轻。
3.缺氧缺血后大鼠脑组织免疫组化染色MBP阳性细胞百分率降低,APP、GFAP阳性细胞百分率增高。给予rHuEPO、GM1、NGF治疗后,术后72h、7d MBP阳性细胞百分率较NS组增高,术后72h、7d、26d APP阳性细胞百分率较NS组降低,术后48h、72h、7d、26d GFAP阳性细胞百分率较NS组降低,差异有显著性意义(P<0.05)。
4.30日龄时, NS组、EPO组、GM1组和NGF组大鼠反应迟钝、自主活动减少,灵活性、稳定性降低。NS组大鼠悬吊、斜坡和旷场试验的结果均差于假手术组,差异有显著性意义(P<0.05);EPO组、GM1组和NGF组大鼠悬吊、斜坡和旷场试验的结果均优于NS组,差异有显著性意义(P<0.05)。
结论:
采用4日龄SD大鼠双侧颈总动脉结扎术可成功建立早产儿脑白质损伤动物模型;早期给予EPO、GM1或NGF干预治疗能够促进大鼠的体格生长和脑白质损伤的修复,改善其神经行为功能。
Objective:
To establish a 4-day-old SD rat animal model of white matter damage, and observe the changes of pathological morphology and neurobehavioral function of the newborn rats after given early treatment with recombinant human erythropoietin (rHuEPO), monosialotetrahexosylganglioside (GM1), or nerve growth factor (NGF). To discuss the neural protect effects of rHuEPO, GM1 and NGF on newborn rats with ischemia-hypoxia white matter damage, and provide evidence of early treatment on preterm infants.
Methods:
Totally 290 4-day-old SD rats were randomly divided into 5 groups: sham-operated group, saline (NS) group, EPO group, GM1 group and NGF group. The sham-operated group were only cut open the neck skin and separated the bilateral carotid arteries without occlusion; and the other four groups were subjected to bilateral carotid artery occlusion (BCAO), after that were separately intraperitoneally injected NS 0.01 ml/g, EPO 5 IU/g, GM1 0.02 mg/g, NGF 2 IU/g; GM1 and NGF were repeatedly injected every 24h, totally given 5 doses. The rats were separately killed at 24h, 48h, 72h, 7d and 26d post-operation. After routine H-E dyeing, light microscopy was used to observe brain pathological changes. Immunohistochemistry methods were used to detect the expression of myelin basic protein (MBP),β-amyloid precursor protein (β-APP) and glial fibrillary acidic protein (GFAP) at each observing time-point post-operation. Hanging test, inclined plane test and open field test were performed on the rats 26 days post-operation.
Results:
1. Weight of four groups of WMD rats were significantly grown slowly. The weight of NS group, EPO group, GM1 group and NGF group were significantly lower than sham-operated group at each observing time-point post-operation (P<0.05). But the weight of EPO group was significantly higher than that of NS group at 7d and 26d post-operation, and the weight of NGF group was significantly higher than that of NS group at 26d post-operation(P<0.05).The weight of GM1 group had no significant difference compared with NS group at each observing time-point post-operation(P>0.05).
2. After ischemia-hypoxia, light microscopy showed periventricular white matter damage, included cell swollen, necrosis and apoptosis, tissue loose and lateral ventricle enlarging. Under light microscopy, the pathological changes of EPO group, GM1 group and NGF group had no obvious differences between them; but when compared with NS group, the range of necrosis was smaller at 72h post-operation, and the extent of lateral ventricle enlarging was smaller at 7d and 26d post-operation.
3. After ischemia-hypoxia, the immunohistochemistry dyeing showed that the percentage of MBP positive cells was decreased, andβ- APP, GFAP positive cells percentages were increased. After treated with rHuEPO, GM1, NGF, the percentage of MBP positive cells increased significantly than that of NS group at 72h or 7d post-operation; APP positive cells percentage decreased significantly than that of NS group at 72h, 7d or 26d post-operation; GFAP positive cells percentage decreased significantly than that of NS group at 48h, 72h, 7d or 26d post-operation(P<0.05).
4. When 30-day-old, the NS group, EPO group, GM1 group and NGF group rats responsed stolidly, their autonomic acivities reduced, flexibility and stability decreased. The results of hanging test, inclined plane test and open field test of NS group were significantly worse than those of sham-operated group(P<0.05). The results of hanging test, inclined plane test and open field test of EPO group, GM1 group and NGF group were significantly better than those of NS group. (P<0.05)
Conclusion:
Using 4-day-old SD rat with BCAO, an animal model of white matter damage can be successfully set up. Early treatment with rHuEPO, GM1 or NGF can improve the rat’s growth and repair of WMD, and ameliorate the rat’s neurobehavioral function.
引文
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[1]周丛乐.早产儿脑白质损伤[J].继续医学教育, 2006, 20(17): 75-77.
[2] Boylan GB, Young K, Panerai RB, et al. Dynamic cerebral auto regulation in sick newborn infants[J]. Pediatr Res, 2000, 48(1): 12-17.
[3] Back SA, Luo NL, Borenstein NS, et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury[J]. J Neurosci, 2001, 21(4): 1302-1312.
[4] Hagberg H, Peebles D, Mallard C. Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults[J]. Ment Retard Dev Disabil Res Rev, 2002, 8(1): 30-38.
[5] Duncan JR, Cock ML, Scheerlinck JP, et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus[J]. Pediatr Res, 2002, 52(6): 941-949.
[6] Yanowitz TD, Jordan JA, Gilmour CH, et al. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations[J]. Pediatr Res, 2002, 51(3): 310-316.
[7] Drobyshevsky A, Song SK, Gamkrelidze G, et al. Developmental changes in diffusion anisotropy coincide with immature oligodendrocyte progression and maturation of compound action potential[J]. J Neurosci , 2005, 25(25): 5988-5997.
[8]沙彬,周文浩.早产儿脑室周围白质软化与少突胶质细胞损伤机制[J].中国新生儿科杂志, 2008, 23(1): 57-60.
[ 9 ] McQuillen PS, Sheldon RA, Shatz CJ, et al. Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia[J]. J Neurosci, 2003, 23(8): 3308-3315.
[ 10 ] Mizuno K, Hida H, Masuda T, et al. Pretreatment with low doses of erythropoietin ameliorates brain damage in periventricular leukomalacia by targeting late oligodendrocyte progenitors: a rat model[J]. Neonatology, 2008, 94(4): 255-266.
[ 11 ] Uehara H, Yoshioka H, Kawase S, et al. A new model of white matter injury in neonatal rats with bilateral carotid artery occlusion[J]. Brain Res, 1999, 837(1-2): 213-220.
[ 12 ] Lin S, Rhodes PG, Lei M, et al. alpha-Phenyl-n-tert-butyl-nitrone attenuates hypoxic ischemic white matter injury in the neonatal rat brain[J]. Brain Res, 2004, 1007(1-2): 132-141.
[ 13 ] Derrick M, Luo NL, Bregman JC, et al. Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy[J]? J Neurosci, 2004, 24(1): 24-34.
[ 14 ] Riddle A, Luo NL, Manese M, et al. Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury[J]. J Neurosci, 2006, 26(11): 3045-3055.
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