The role of thrombin and thrombin receptors in the brain

The serine protease thrombin is generated from its zymogen prothrombin. Both thrombin and prothrombin have been detected locally in the brain. Emerging evidence demonstrates that thrombin exerts physiological and pathological functions in the central nervous system. During brain development, thrombin regulates cell proliferation, differentiation, and migration. Thrombin is also involved in synaptic organization and synaptic plasticity in normal brain. In the brain injured in neurodegenerative disorders, the activity of thrombin is modulated and thrombin mediates the dual opposite effects. Low concentrations of thrombin rescue neural cells from death after brain insults. In contrast, thrombin at high concentrations exacerbates brain damage. The cellular functions of thrombin are mainly regulated by G protein-coupled protease-activated receptors (PARs). Thrombin can signal to PAR₁, PAR₃, and PAR₄. PAR₁ has been shown to mediate extensively thrombin-induced neurodegeneration and neuroprotection in the brain. Therefore, thrombin and thrombin receptors represent novel therapeutic targets for treating neurodegenerative diseases.