Thrombin-receptor activation and thrombin-induced brain tolerance

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Previous studies demonstrated that low-dose thrombin pretreatment (thrombin preconditioning) reduces brain edema and infarct volume.
• The mechanism underlying thrombin preconditioning, specifically the role of the thrombin receptor, remained unclear.

Purpose of the Study:

• To investigate if thrombin preconditioning involves the activation of the thrombin receptor (protease-activated receptor).
• To elucidate the signaling pathways mediating the neuroprotective effects of thrombin preconditioning.

Main Methods:

• In vivo studies utilized thrombin-receptor antagonist RPPGF and agonist to assess brain tolerance and edema.
• In vitro experiments examined cell viability, lactate dehydrogenase release, and protein kinase activation under various thrombin concentrations.
• Western blot analysis was used to detect p44/42 mitogen-activated protein kinase activation.

Main Results:

• Thrombin-induced brain tolerance was abolished by the thrombin-receptor antagonist RPPGF in vivo.
• Thrombin-receptor agonist pretreatment reduced edema, and thrombin preconditioning protected cells from high-dose thrombin-induced damage in vitro.
• p44/42 mitogen-activated protein kinases were activated by thrombin preconditioning, and their inhibition abolished the protective effect.

Conclusions:

• Thrombin-induced brain tolerance is mediated, in part, by the activation of the thrombin receptor.
• Activation of the thrombin receptor in the brain exhibits neuroprotective properties.
• The protective effects of thrombin preconditioning are transmitted via the p44/42 mitogen-activated protein kinase signaling pathway.