Cytotoxic actions of FTY720, a novel immunosuppressant, on thymocytes and brain neurons dissociated from the rat.
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 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.
Oyama
Y
Y
Laboratory of Cellular Signalling, Faculty of Integrated Arts and Sciences, The University of Tokushima, Japan.
Chikahisa
L
L
Kanemaru
K
K
Nakata
M
M
Noguchi
S
S
Nagano
T
T
Okazaki
E
E
Hirata
A
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D004074:Digitoxin / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence; D013110:Sphingosine / Q000031:analogs & derivatives; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D004074:Digitoxin; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine