促红细胞生成素抑制大鼠创伤性脑水肿形成

EPO inhibits the formation of traumatic brain edema in rats

目的探讨促红细胞生成素(erythropoietin,EPO)对大鼠创伤性脑水肿的影响及其的潜在分子机制。方法取SD大鼠90只,随机分为假手术组,创伤组和EPO组。创伤组:制作改进式Feeney's脑创伤模型;EPO组:伤后给大鼠腹腔注射重组人促红细胞生成素(5000 IU/kg)。伤后24 h,72 h和120 h,使用平衡木法评定各组大鼠行为学评分。伤后72 h时,检测各组大鼠脑含水量,脑组织胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)的磷酸化水平、水通道蛋白4(aquaporin 4,AQP4)mRNA和蛋白表达水平。结果在伤后各时间点,EPO组大鼠神经功能障碍的行为学评分也较创伤组有明显降低(均P<0.05)。伤后脑组织含水量由假手术组的78.76%±0.65%上升至创伤组的81.26%±0.40%(P<0.01),EPO组脑含水量则降低至79.71%±0.59%(与创伤组比较P<0.01)。与假手术组比较,创伤组ERK磷酸化的水平在伤后72 h明显上升(P<0.01),EPO组伤后ERK磷酸化水平则明显低于创伤组(0.369±0.046 vs.0.815±0.127,P<0.01);AQP4 mRNA和蛋白在伤后的表达水平均较假手术组明显增高(均P<0.01),EPO组AQP4 mRNA和蛋白的表达水平较创伤组均显著下降(均P<0.01)。结论EPO可抑制大鼠脑创伤后ERK信号通路的过度激活及下游AQP4的过表达,减轻大鼠的创伤性脑水肿。

Objective To investigate the effects and mechanism of erythropoietin(EPO)in traumatic brain edema.Methods Ninety healthy adult male SD rats were randomly divided into Sham group,Trauma group and EPO group.Modified Feeney's brain trauma model was made in trauma group.The rats in EPO group were intraperitoneally injected with recombinant human erythropoietin(5000 IU/kg)after brain trauma.The behavioral scores were evaluated by the balance beam method at 24 h,72 h and 120 h after injury.The brain water content,phosphorylation levels of extracellular regulated protein kinases(ERK)and expression levels of aquaporin 4(AQP4)mRNA and protein were examined at 72 h after injury.Results The behavioral scores of neurological dysfunction were significantly lower in EPO group than that in trauma group at each time point after injury(all P<0.05).The water content of brain tissue was higher in trauma group(81.26%±0.40%)compared with sham group(78.76%±0.65%)while was lower in EPO group(79.71%±0.59%)compared with trauma group(P<0.01).The ERK phosphorylation level and mRNA and protein levels of AQP4 were significantly higher(P<0.01)in the trauma group compared with sham group at 72 hours after injury.ERK phosphorylation level was lower in the EPO group than in trauma group(0.369±0.046 vs.0.815±0.127,P<0.01).The expression levels of AQP4 mRNA and protein were significantly lower in the EPO group than in trauma group(P<0.01).Conclusion EPO can inhibit the overactivation of ERK signal pathway,attenuate the overexpression of downstream AQP4 and reduce the traumatic brain edema in rats after brain injury.