The effect of silyl substituted methotrexate in the treatment of experimental allergic encephalomyelitis in rats mediated by T-line cells.

The effect of methotrexate and of silyl-methotrexate were compared in the treatment of experimental allergic encephalomyelitis (EAE) mediated by T-line lymphocytes. It was demonstrated that, during the first three days after cell transfer, no difference between methotrexate and its silyl derivative could be seen. At a time when the cytotoxic lymphoblasts must have penetrated the blood brain barrier, only silyl methotrexate was able to prevent severe paralysis and death of the animals. It is suggested that the effect of N,N,O,O-Tetrakis (t-butyldimethylsilyl)-methotrexate, (N-4-N-(2,3-bis-t-butyldimethylsilyl-amino-6-pteridinyl-methyl)- methylamino-benzoyl-glutamic acid-bis-(t-butyldimethylsilyl)-ester), depends on the increased lipid solubility and permeability of the blood brain barrier of silylated drugs.

[Mercaptopurine and silylated mercaptopurine the treatment of experimental allergic encephalomyelitis]. / Mercaptopurin und silyliertes Mercaptopurin in der Behandlung der experimentell allergischen Enzephalomyelitis.

The therapeutic effects of mercaptopurine (6-mercaptopurine, 6-MP) and a silylated derivative (6-trimethylsilylthio-9-trimethyl-silylpurine, S-MP) were compared on the course of T lymphocyte line mediated experimental allergic encephalomyelitis (t-EAE). This transferred EAE is a passively induced model disease in Lewis rats easy to elicit, reliably reproducible and characterized by a dose-dependent lethality. If given at different points in single injections the silicon derivative is shown to be more efficient than 6-MP (43/125 surviving animals compared to 26/129), severity of disease is attenuated and number of survivors increased. Silylation is able to improve blood-brain barrier and cellular permeability; S-MP suppresses intrathecal inflammatory cells more effectively than the original immunosuppressant.

T lymphocyte line-mediated experimental allergic encephalomyelitis--a pharmacologic model for testing of immunosuppressive agents for the treatment of autoimmune central nervous system disease.

An acute form of transferred experimental allergic encephalomyelitis was induced by injection of activated, myelin basic protein-specific T cell line lymphocytes. The course of the disease as a function of the dose of cytotoxic cells was investigated, and the effect of i.p. and i.v. application of methotrexate on mortality and morbidity was determined. Depending on the time of administration, beneficial therapeutic effects could be seen as early as 1 week. Survival of animals that had received a lethal dose of 15 to 20 X 10(6) cells/kg proved to be the most valuable parameter. T lymphocyte line-mediated experimental allergic encephalomyelitis is a predictable acute central nervous system model disease that does not require antigen depots or cell donor animals.