Thrombin-induced tolerance against oxygen-glucose deprivation in astrocytes: role of protease-activated receptor-1.

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.