Role Of Protease-activated Receptor On Thrombin-induced Brain Injury And Neurogenesis

Intracerebral hemorrhage (ICH), which a serious threat to human health disease, is a subtype of stroke that may cause significant morbidity and disability. Recent studies have indicated that thrombin contributes to brain edema and neuronal degeneration after ICH. Thrombin has a central role in the mechanisms of ICH-induced secondary brain injury. The effect of thrombin is believed to act by activation of protease activated receptors (PARs) mediated pathway and non-receptor mediated pathway. PARs mediated pathway is involved in multiple signal transduction and cell surface receptor, the mechanisms of PAR-mediated signal transduction still need to further attention. Because of high disability, the treatment of neurological impairment after ICH appear to be more important. Neurogenesis has been demonstrated in ICH, but the effects of thrombin activated PARs to neurogenesis have not been well investigated.Objective:To study the role of protease-activated receptors on thrombin-induced brain injury in rats, and analyze the relationship between thrombin and protease-activated receptors and neurogenesis in rats. It would be provided that the experimental evidence for treatment of secondary brain injury and neurological impairment after ICH.Methods:(1)90adult male SD rats were randomly divided into5groups:saline group, thrombin group, PAR-1agonist group, PAR-3agonist group and PAR-4agonist group. Each group were randomly divided into3time phases:Id,3d and7d. Saline (10μl), thrombin (5U), PAR-1agonist (10nmol), PAR-3agonist (10nmol) and PAR-4agonist (lOnmol) were stereotactically injected into right hippocampus.(2) At Id,3d or7d after injection, the area of the hippocampus was determined by using HE staining, the density and morphology of astrocyte was detected by using GFAP staining, degenerated neurons were detected by using Flouro-Jade C staining, and the neurogenesis were examined by using DCX staining.Results:(1) Compared to the saline group, the area of the hippocampus significantly increased at1-3d and decreased at7d after the injection of thrombin and PAR-1agonist. At1d,3d and7d after injection, PAR-3agonist group and PAR-4agonist group had no affect on the area of the hippocampus.(2) At1d after injection, the density of astrocyte and Flouro-Jade C positive cells in thrombin group and PAR-1agonist group were more than that in saline group, at3d, they reached their maximum, at7d, they were still more than that in saline group. At1d,3d and7d after injection, PAR-3agonist group and PAR-4agonist group had no affect on the density of astrocyte and Flouro-Jade C positive cells.(3) At Id after injection, the density of DCX-positive cells in thrombin group and PAR-1group were no significant changed, but they began increased at3d and still more than that in saline group at7d. At1d,3d and7d after injection, PAR-3agonist group and PAR-4agonist group had no affect on the density of DCX-positive cells.Conclusion:(1) The activation of PAR-1may be related to the thrombin-induced brain injury.(2) Thrombin may induce neurogenesis in rat hippocampus, and the activation of PAR-1may be involved in the neurogenesis.