MAPK信号通路在创伤性脑损伤中的作用

目的通过建立小鼠创伤性脑损伤(TBI)模型,研究丝裂原活化蛋白激酶(MAPKs)通路中的细胞外调节蛋白激酶1/2(ERK1/2)通路、JNK通路和p38通路的激活及在TBI中的作用及机制。方法建立小鼠TBI模型,通过Western blot检测ERK1/2、JNK和p38的相对磷酸化水平,确定TBI后MAPK通路的激活情况;分别加入ERK1/2通路抑制剂(PD98059,500μmol/L)、JNK通路抑制剂(SP600125,500μmol/L)和p38通路抑制剂(SB203580,500μmol/L),通过脑干湿重检测、神经功能学评分和TUNEL染色评估不同抑制剂对TBI的作用,并通过Western blot检测ERK1/2、JNK和p38的相对磷酸化水平,明确ERK1/2通路、JNK通路和p38通路之间的相互调节作用。结果 TBI可分别引起ERK1/2通路、JNK通路和p38通路的激活;抑制ERK通路和JNK通路可减轻TBI引起的脑水肿、神经功能损伤和细胞凋亡,而抑制p38通路则加重TBI引起的脑水肿、神经功能损伤和细胞凋亡;抑制JNK通路可减少ERK1/2的相对磷酸化水平,而抑制p38通路可增加ERK1/2的相对磷酸化水平。结论 TBI后,ERK1/2通路和JNK通路的激活发挥促进损伤形成的作用,而p38通路的激活则起到神经保护的作用;ERK1/2通路的激活受到JNK通路的促进和p38通路的抑制,表明MAPK通路之间存在相互调节。

Effects of MAPK pathways on traumatic brain injury

Objective To investigate the effect of mitogen-activated protein kinases （MAPK） pathways such as extracellular regulated protein kinases1/2 （ERK1/2） pathway, JNK pathway, and p38 pathway on traumatic brain injury （TBI） by using in vivo TBI model. Methods After TBI, phosphorylation of ERK1/2, JNK, and p38 was detected by Western blot; effects of ERK1/2 pathway inhibitor （PD98059, 500 μmol/L）, JNK pathway inhibitor （SP500125, 500μmol/L）, and p38 pathway inhibitor （SB2ff5580, 590 μmol/L） on TBI were measured by water content detection, neurological severity score, and TUNEL assay and interactions between MAPK pathways were determined by Western blot. Results TBI differentially activated ERK1/2 pathway, iNK pathway, and p38 pathway; inhibition of ERK1/2 pathway or JNK pathway attenuated TBI-induced brain edema, neurological deficits, and apoptosis, while inhibition of p38 pathway aggravated TBI-induced brain edema, neurological deficits, and apoptosis; inhibition of JNK pathway reduced the relative phosphorylation of ERK1/2, whereas inhibition of of p38 pathway elevated the relative phosphorylation of ERK1/2. Conclusion After TBI, activation of ERK1/2 pathway and JNK pathway protnotes the formtion of brain edema, neurological deficits, and apoptosis, while activation of p38 pathway plays a ncuroprotective role in TBI; activation of ERK1/2 pathway is promoted by JNK pathway but inhibited by p38 pathway, indicating that there are interactions between different MAPK pathways.