THROMBIN RECEPTOR ACTIVATION PROTECTS NEURONS AND ASTROCYTES FROM CELL-DEATH PRODUCED BY ENVIRONMENTAL INSULTS

Thrombin is a multifunctional serine protease that is rapidly produced from prothrombin at sites of tissue injury and catalyzes the final st eps in blood coagulation, Thrombin also regulates gene expression and process outgrowth in neurons and astrocytes and stimulates proliferati on of astrocytes, Since thrombin is produced immediately upon breakdow n of the blood-brain barrier we examined its effects on astrocytes and neurons cultured under conditions which resemble those found in vivo following cerebrovascular injury, These studies showed that thrombin m arkedly protected rat primary astrocytes from cell death induced by hy poglycemia or oxidative stress, Thrombin also protected rat primary hi ppocampal neurons from cell death produced by hypoglycemia or growth s upplement deprivation, Synthetic peptides which directly activate the thrombin receptor also protected astrocytes and neurons from these env ironmental insults, demonstrating that the thrombin effects were media ted through the thrombin receptor, In contrast to these results with s tressed cells, high concentrations of thrombin killed both astrocytes and neurons cultured under normal conditions, All of the effects of th rombin on astrocytes and neurons were blocked by the brain thrombin in hibitor, protease nexin-1 (PN-1), This shows that the effects required the proteolytic activity of thrombin and is consistent with the known proteolytic mechanism by which thrombin activates its receptor, These results indicate that thrombin and PN-1 may regulate the viability of both astrocytes and neurons in early moments following trauma to the CNS or other conditions that alter the blood-brain barrier.