Suppression of experimental autoimmune encephalomyelitis by a new specific leukotriene biosynthesis inhibitor.
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Animals↗
Biomedical subjects
L Mehlber
Publications and source records attributed to L Mehlber.
Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients.
The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.
Adult↗
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.
Animals↗
Suppression of experimental autoimmune encephalomyelitis by sulfasalazine.
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Animals↗
Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition.
The release of leukotriene C4 (LTC4), an important 5-lipoxygenase product of the arachidonic acid metabolism from polymorphonuclear leucocytes (PMNLs) of guinea pigs with experimental allergic encephalomyelitis (EAE), the animal model of MS, has been found to be significantly increased compared with healthy animals. Subsequently, the dual cyclo-oxygenase and 5-lipoxygenase inhibitor BW755C was applied to 15 guinea pigs with EAE. Two control groups (15 each) were treated with the cyclo-oxygenase inhibitor indomethacin or physiological saline, respectively. In the BW755C treated group, no animal developed symptoms of the disease in contrast to, respectively, 5 and 3 animals in the 2 other groups. Histological examination of the CNS revealed a highly significantly lower inflammation score in the BW755C treated animals, and the release of LTC4 from PMNLs was highly significantly decreased in this group compared with each of the others. The findings suggest that the vascular permeability enhancing LTC4 plays a pathogenetic role in EAE and indicate that inhibition of this sulfidopeptide leukotriene suppresses the disease. Therefore, the application of leukotriene inhibitors could contribute to the future treatment of MS.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Leukotrienes B4 and C4 in MS.
Release of leukotriene B4 (LTB4) and leukotriene C4 (LTC4) from neutrophils and platelet-neutrophil suspensions in response to ionophore A23187 was measured in 12 multiple sclerosis (MS) patients and 8 healthy volunteers. LTC4 release from neutrophils, as well as from platelet-neutrophil suspensions, was significantly decreased in MS patients compared with the controls. There was no significant difference in the release of LTB4 between MS patients and controls. The findings suggest that permanent stimulation of platelets and neutrophils e.g., by encephalitogenic peptide leads to continuous LTC4 release with subsequent depletion of intracellular substrates serving as precursors for the formation of 5-lipoxygenase products. Since the target of microvascular actions of LTC4 are postcapillary venules, the release of this sulfidopeptide leukotriene might play a pathogenetic role in the formation of MS lesions.
Adult↗
Encephalitogenic peptide and platelet aggregation in multiple sclerosis.
Platelet aggregation (PA) stimulated by encephalitogenic peptide (EP) and PA induced by ADP were measured in 83 multiple sclerosis (MS) patients and 70 control subjects with other neurological diseases (OND). EP-stimulated PA was significantly increased in MS patients as compared with the controls. There was no significant difference in ADP-induced PA between patients with MS and OND. The results are discussed in terms of EP-stimulated platelets playing a role in the pathogenesis of MS by affecting the venular permeability of the brain.
Adenosine Diphosphate↗