Thrombin-receptor activation and thrombin-induced brain tolerance.
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.
Jiang
Yajun
Y
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109-0532, USA.
Wu
Jimin
J
Hua
Ya
Y
Keep
Richard F
RF
Xiang
Jianming
J
Hoff
Julian T
JT
Xi
Guohua
G
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019194:Ischemic Preconditioning; D008297:Male; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018179:Receptors, Thrombin / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D018179:Receptors, Thrombin; D013917:Thrombin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one