CYTOTOXIC ACTIONS OF FTY720, A NOVEL IMMUNOSUPPRESSANT, ON THYMOCYTESAND BRAIN NEURONS DISSOCIATED FROM THE RAT

Effects of FTY720 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol H Cl), a novel immunosuppressant, were examined on neurons and thymocyte s respectively dissociated from rat brains and thymus glands using a f low cytometer to see if FTY720 exerts cytotoxic actions not only on sp leen cells as previously reported but also on the other cells. FTY720 at a concentration of 10 mu M deteriorated almost all of the thymocyte s, while it was not the case for brain neurons. FTY720 increased the i ntracellular concentration of Ca2+ ([Ca2+](i)) of thymocytes in both t he presence and absence of external Ca2+, although the [Ca2+](i) incre ased by FTY720 in the presence of external Ca2+ was much greater than that in the absence of external Ca2+. Thus, FTY720 may increase the me mbrane permeability of Ca2+ and release Ca2+ from intracellular Ca2+ s tores in thymocytes. Furthermore, the number of thymocytes stained wit h ethidium, a dye impermeant to intact membranes, time-dependently inc reased after drug application. Therefore, FTY720 at concentrations of 3 - 10 mu M non-specifically increases the membrane permeability of th ymocytes, resulting in necrotic cell death, although FTY720 at micromo lar concentrations was reported to induce apoptosis of spleen cells.