Thrombin-induced tolerance against oxygen-glucose deprivation in astrocytes: role of protease-activated receptor-1.
Thrombin-induced tolerance against oxygen-glucose deprivation in astrocytes: role of protease-activated receptor-1.
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发表时间：
2018-02
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通讯作者：
Xuhui Bao;Y. Hua;R. Keep;G. Xi
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作者：
Xuhui Bao;Y. Hua;R. Keep;G. Xi
我们以前的研究发现，小剂量凝血酶(凝血酶预适应，TPC)预处理可缩小在体局灶性脑缺血后的脑梗塞体积，减轻脑水肿，并对体外氧糖剥夺(OGD)诱导的神经元死亡具有保护作用。在这项研究中，我们发现TPC(0.5或1U/ml凝血酶作用24小时)对OGD诱导的星形胶质细胞死亡具有保护作用，这种保护作用是通过蛋白酶激活的受体-1(PAR-1)和p44/42丝裂原活化蛋白激酶(MAPK)/p90核糖体S6激酶(P90RSK)/热休克蛋白25(HSP25)途径实现的。相反，在PAR-1 KO小鼠星形胶质细胞中，TPC没有保护作用，也不显著地磷酸化p44/42MAPK或p90RSK或上调HSP25。P44/42MAPK的抑制剂PD98059可阻断凝血酶诱导的WT小鼠星形胶质细胞耐受，并上调p90RSK和HSP25的磷酸化水平。此外，p90RSK的抑制剂SL0101可阻断凝血酶诱导的保护和WT小鼠星形胶质细胞HSP25的上调。这些结果提示TPC诱导的缺血星形胶质细胞耐受可能是通过激活凝血酶受体PAR-1和下游的p44/42 MAPK/p90RSK/HSP25通路实现的。
Our previous studies have found that pretreatment with a low dose of thrombin (thrombin preconditioning, TPC) reduces infarct volume and attenuates brain edema after focal cerebral ischemia in vivo and protects against the neuronal death induced by oxygen glucose deprivation (OGD) in vitro. In this study, we found that TPC (24 hours exposure to 0.5 or 1 U/ml thrombin) protects against OGD-induced astrocyte death, and that such protection is through protease activated receptor-1 (Par-1) and the p44/42 mitogen activated protein kinase (MAPK)/p90 ribosomal S6 kinase (p90RSK)/heat shock protein 25 (HSP25) pathway. In contrast, in Par-1 KO mouse astrocytes, TPC had no protective effect and it did not significantly phosphorylate p44/42 MAPK or p90RSK or upregulate HSP25. PD98059, an inhibitor of p44/42 MAPK, blocked thrombin-induced tolerance as well as upregulation of phosphorylated p90RSK and HSP25 in WT mouse astrocytes. Furthermore, SL0101, an inhibitor of p90RSK, blocked thrombin-induced protection and the HSP25 upregulation in WT mouse astrocytes. These results suggest that TPC-induced tolerance in ischemic astrocytes may be through activation of thrombin receptor Par-1 and a downstream p44/42 MAPK/p90RSK/HSP25 pathway.