Thrombin-Receptor Activation and Thrombin-Induced Brain Tolerance

Abstract

The authors previously found that pretreatment with a low dose of thrombin attenuates the brain edema induced by a large dose of thrombin or an intracerebral hemorrhage, and reduces infarct volume after focal cerebral ischemia (i.e., thrombin preconditioning). This study investigated whether thrombin preconditioning is caused by activation of the thrombin receptor, also called protease-activated receptor. In the in vivo studies, thrombin-induced brain tolerance was eliminated by RPPGF (Arg-Pro-Pro-Gly-Phe), a thrombin-receptor antagonist. Pretreatment with a thrombin-receptor agonist reduced the amount of edema induced by a large dose of thrombin infused into the ipsilateral basal ganglia 7 days later (81.3 +/- 0.7% vs. 82.6 +/- 0.8% in the control, P < 0.05). In the in vitro study, low doses of thrombin (1 or 2 U/mL) did not induce cell death. However, doses greater than 5 U/mL resulted in dose-dependent lactate dehydrogenase release (P < 0.01). Thrombin and thrombin receptor-activating peptide preconditioning reduced lactate dehydrogenase release induced by a high dose of thrombin (10 and 20 U/mL), whereas RPPGF blocked the effect of thrombin preconditioning in vitro. Western blots indicated that p44/42 mitogen-activated protein kinases were activated after thrombin preconditioning. Finally, inhibition of p44/42 mitogen-activated protein kinases activation by PD98059 abolished the thrombin-preconditioning effect. Results indicate that thrombin-induced brain tolerance is in part achieved through activation of the thrombin receptor. Activation of the thrombin receptor in the brain may be neuroprotective. The protective effect of thrombin preconditioning is achieved through the p44/42 mitogen-activated protein kinase signal-transduction pathway.

Differential Ca2+signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells

“…One of the most prominent features of the brain endothelial cell barrier is a very low permeability to macromolecules and solutes compared with endothelial cells of nonbrain origin. Thrombin activation of endothelial cells of nonbrain origin is associated with a breakdown of endothelial barrier functions, gap formation, and increased permeability (8,23). A decrease of transendothelial monolayer resistance is one of the signs of endothelial barrier dysfunction in response to thrombin stimulation (8,23,30,39).…”

“…Thrombin activation of endothelial cells of nonbrain origin is associated with a breakdown of endothelial barrier functions, gap formation, and increased permeability (8,23). A decrease of transendothelial monolayer resistance is one of the signs of endothelial barrier dysfunction in response to thrombin stimulation (8,23,30,39). We used a real-time TER measuring system to investigate the effects of thrombin and PAR1-AP on HBMEC.…”

The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing

“…It is also interesting that intracerebral hemorrhage (with resultant thrombin production) in or near the nigrostriatal tract, has been found to produce L-DOPA responsive behavioral deficits similar to those observed in PD [19,30]. Many thrombin effects are receptor mediated, involving protease-activated receptor (PAR) activation [21]. Mice deficient in PAR-1 are protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurotoxicity [16], which causes PD-like effects in humans and animals [23,24].…”

“…Such cross-tolerance among other injury models is known to occur [15]. Although the mechanisms of protection remain to be determined, the preconditioning effects of thrombin depend on activation of the protease-activated receptor-1 (PAR-1) [4], a thrombin receptor linked to injury tolerance [21].…”

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

“…147 Although the exact mechanism by which thrombin exerts its neuroprotective effects is unknown, it is believed to be due to the activation of PARs, production of heat shock proteins, and upregulation of endogenous thrombin inhibitors. 56,62,144,147 Additionally, thrombin preconditioning has been shown to increase levels of hypoxia inducible factor-1α, transferrin, and transferrin receptor, increasing brain tolerance to erythrocyte-and iron-mediated injury. 52 Further research elucidating the mechanisms of this protective effect are needed for the development of therapeutic strategies aimed to enhance this effect.…”