Cytotoxic Actions of FTY720, a Novel Immunosuppressant, on Thymocytes and Brain Neurons Dissociated From the Rat

Abstract

Effects of FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1, 3-propanediol HCl), a novel immunosuppressant, were examined on neurons and thymocytes respectively dissociated from rat brains and thymus glands using a flow cytometer to see if FTY720 exerts cytotoxic actions not only on spleen cells as previously reported but also on the other cells. FTY720 at a concentration of 10 μM deteriorated almost all of the thymocytes, while it was not the case for brain neurons. FTY720 increased the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) of thymocytes in both the presence and absence of external Ca²⁺, although the [Ca²⁺]_i increased by FTY720 in the presence of external Ca²⁺ was much greater than that in the absence of external Ca²⁺. Thus, FTY720 may increase the membrane permeability of Ca²⁺ and release Ca²⁺ from intracellular Ca²⁺ stores in thymocytes. Furthermore, the number of thymocytes stained with ethidium, a dye impermeant to intact membranes, time-dependently increased after drug application. Therefore, FTY720 at concentrations of 3 – 10 μM non-specifically increases the membrane permeability of thymocytes, resulting in necrotic cell death, although FTY720 at micromolar concentrations was reported to induce apoptosis of spleen cells.