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目的探讨不同剂量促红细胞生成素(EPO)对缺氧缺血性脑损伤(HIBD)新生大鼠脑组织水通道蛋白4(AQP-4)表达的影响。方法选取7日龄SD大鼠100只。随机分为假手术组、对照组、EPO低剂量组、EPO中剂量组、EPO高剂量组,每组20只。假手术组仅分离右颈总动脉,不作缺氧缺血(HI)处理,也不给予药物。EPO低剂量组、EPO中剂量组、EPO高剂量组和对照组分离右颈总动脉并结扎,后置于80 mL·L-1氧气和920 mL·L-1氮气2 h制备新生大鼠HIBD模型。EPO低剂量组、EPO中剂量组、EPO高剂量组在HI后0 h、1 d、3 d、5 d分别腹腔注射EPO 1 000 IU.kg-1、2 500 IU.kg-1、5 000 IU.kg-1,对照组和假手术组腹腔注射等体积9 g.L-1盐水。每组随机取10只于HI后3 d、7 d处死。应用免疫组织化学方法和计算机图像分析技术检测其脑组织AQP-4表达的变化。结果 1.与对照组3 d时[(42.60±4.82)个]比较,假手术组、EPO低剂量组、EPO中剂量组、EPO高剂量组AQP-4阳性细胞数明显少[(26.60±4.67)个、(36.60±3.97)个、(20.80±7.90)个、(23.00±9.60)个],EPO中剂量和EPO高剂量组较EPO低剂量组明显少,差异均有统计学意义(Pa<0.05),假手术组、EPO中剂量组、EPO高剂量组组间比较差异均无统计学意义(Pa>0.05);2.与对照组7 d时[(46.20±5.07)个]比较,假手术组、EPO中剂量组、EPO高剂量组AQP-4阳性细胞数仍明显减少[(16.80±4.65)个、(33.20±4.38)个、(25.60±7.63)个],EPO高剂量组较EPO中剂量组、EPO中剂量组较EPO低剂量组少,差异均有统计学意义(Pa<0.05)。EPO低剂量组、EPO中剂量组、EPO高剂量组HE染色显示脑组织的病理损伤程度低于对照组。结论EPO可下调HIBD新生大鼠AQP-4表达,从而有效减轻脑水肿,发挥神经保护作用,且呈剂量依赖效应,中剂量、高剂量作用强于低剂量。
Objective To investigate the effect of different doses of erythropoietin (EPO) on the expression of aquaporin 4 (AQP-4) in brain tissue of neonatal rats with hypoxic-ischemic brain damage (HIBD). Methods 100 SD rats of 7 days old were selected. Randomly divided into sham operation group, control group, EPO low dose group, EPO middle dose group, EPO high dose group, 20 rats in each group. Sham-operation group only isolated the right common carotid artery, without hypoxia-ischemia (HI) treatment, nor given drugs. The EPO low dose group, EPO middle dose group, EPO high dose group and control group were separated from the right common carotid artery and ligated with 80 mL · L -1 oxygen and 920 mL · L -1 nitrogen for 2 h to prepare neonatal rat HIBD model. EPO low dose group, EPO medium dose group and EPO high dose group were intraperitoneal injected EPO 1 000 IU.kg-1, 500 IU.kg-1, 000 000 at 0 h, 1 d, 3 d and 5 d after HI IU.kg-1, the control group and sham operation group, intraperitoneal injection of an equal volume of 9 gL-1 saline. Ten rabbits in each group were sacrificed 3 days and 7 days after HI. The changes of AQP-4 expression in brain tissue were detected by immunohistochemistry and computer image analysis. Compared with the control group at 3 d [(42.60 ± 4.82)], the number of AQP-4 positive cells in sham operation group, EPO low dose group, EPO middle dose group and EPO high dose group were significantly less ([26.60 ± 4.67 (36.60 ± 3.97), (20.80 ± 7.90), (23.00 ± 9.60), respectively. Compared with the EPO low dose group, EPO middle dose and EPO high dose group were significantly less, the difference was statistically significant (Pa < 0.05). There was no significant difference between sham operation group, EPO middle dose group and EPO high dose group (P> 0.05); 2. Compared with the control group at 7 d [(46.20 ± 5.07)], The number of AQP-4 positive cells in the EPO high dose group and the EPO middle dose group were still significantly decreased ([(16.80 ± 4.65) vs (33.20 ± 4.38), (25.60 ± 7.63) The middle dose group and EPO middle dose group were less than the EPO low dose group, the difference was statistically significant (Pa <0.05). EPO low dose group, EPO middle dose group, EPO high dose group HE staining showed that the pathological damage of brain tissue is lower than the control group. Conclusion EPO can down-regulate the expression of AQP-4 in neonatal rats with HIBD, thus effectively relieving cerebral edema and exerting neuroprotective effects in a dose-dependent manner. The effects of middle dose and high dose of EPO are stronger than those of low dose.