Jpn. J. Pharmacol. 76 (4), 377-385 (1998)

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

Yasuo Oyama, Lumi Chikahisa (#1), Kaori Kanemaru, Mami Nakata, Sachi Noguchi, Takayuki Nagano, Eisuke Okazaki and Akira Hirata (#2)

Laboratory of Cellular Signalling, Faculty of Integrated Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan
Present address:
(#1) Taiho Pharmaceutical Co., Ltd., Hanno 357-8527, Japan
(#2) Santen Pharmaceutical Co., Ltd., Osaka 533-8651, Japan

Abstract: Effects of FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol HCI), 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 microM 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 microM 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.

Keywords: Brain neuron, Cytotoxic action, Immunosuppressant, Thymocyte, Flow cytometry

Copyrightę The Japanese Pharmacological Society 1998

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