Suppression of experimental autoimmune encephalomyelitis by a new specific inhibitor of leukotriene biosynthesis.
The actions of the specific inhibitor of leukotriene synthesis, 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (L-663, 536, CAS 118414-82-7) were investigated in groups of guinea pigs that had been given both low and high doses of the encephalitogenic stimulant to induce experimental autoimmune encephalomyelitis (EAE). After daily intraperitoneal application over a period of 2 to 3 weeks the substance L-663, 536 (5 mg/kg) largely suppressed the clinical symptoms of EAE in some of the animals. The difference in the clinical symptoms between those animals that had been treated with L-663, 536 and those that had not was observed primarily in the experiment with a high encephalitogenic dose. The onset of progressive paralysis of the hind limbs that was observed in approximately 80% of the control animals only occurred in 40% of the guinea pigs that were treated with L-663, 536. No paresis at all was observed in about 25% of the treated animals. In both laboratory animals studies the CNS inflammatory infiltrates were significantly less extensive in the treated animals than in the respective control groups. The release of leukotrienes B4 and C4 by circulating neutrophil granulocytes in guinea pigs under treatment with L-663, 536 was also significantly reduced--in contrast to the untreated control animals. On the basis of the present results, it may be assumed that the L-663, 536-induced suppression of EAE in guinea pigs is attributable to the inhibition of leukotriene biosynthesis.
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Department of Neurology, Sindelfingen Municipal Hospital (Academic Teaching Hospital of Tübingen University), Fed. Rep. of Germany.
Wildfeuer
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A
Mallinger
J
J
Mehlber
L
L
D000818:Animals; D001921:Brain / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D007211:Indoles / Q000627:therapeutic use*; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010243:Paralysis / Q000517:prevention & control; D013189:SRS-A / Q000096:biosynthesis; D002722:Chlorobenzenes
D007211:Indoles; D020024:Leukotriene Antagonists; D007975:Leukotriene B4; D015289:Leukotrienes; D013189:SRS-A; C060893:MK-886; D002722:Chlorobenzenes