Rabeximod reduces arthritis severity in mice by decreasing activation of inflammatory cells.
OBJECTIVE
The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo.


METHODS
Collagen antibody-induced arthritis (CAIA) is induced by monoclonal collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene.


RESULTS
Rabeximod efficiently prevented arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages. The effect operated downstream of TLR activation as Rabeximod was highly therapeutic in CAIA enhanced through TLR2 stimuli in TLR4 deficient mice. In addition, it was found that the arthritis ameliorating effect of Rabeximod was time dependent, since inhibition of tumour necrosis factor alpha production from macrophages in vitro was more pronounced if administered close to stimulation.


CONCLUSIONS
Rabeximod suppresses arthritis by preventing activation of inflammatory cells, most likely macrophages, in a time dependent fashion, downstream of TLR2 and TLR4 stimulation.
Hultqvist
Malin
M
Medical Inflammation research, C12 BMC, Lund University, Lund, Sweden.
Nandakumar
Kutty Selva
KS
Björklund
Ulf
U
Holmdahl
Rikard
R
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018501:Antirheumatic Agents; D007211:Indoles; D011810:Quinoxalines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C534586:rabeximod