Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injuryto the developing rat brain

Fas/CD95/Apo-1 is a cell surface receptor that transduces apoptotic death s ignals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mecha nism of neuronal loss following hypoxic-ischemic injury to the developing b rain, although the role of Fas in this process has not been studied in deta il. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expresse d in the 14 day old rat brain, with strongest expression in the cortex, hip pocampus and cerebellum. Cross-linking of Fas induced neuronal apoptosis bo th in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. T his death was shown to be caspase dependent in primary neuronal cultures an d was blocked by the selective caspase 8 inhibitor IETD, Finally, cerebral hypoxia-ischemia resulted in a strong lateralised upregulation of Fas in th e hippocampus, that peaked six to twelve hours after the insult and was gre ater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic-ischemic injury to the developing b rain.