Involvement of the peripheral benzodiazepine receptor in the development of rheumatoid arthritis in Mrl/lpr mice.
In this study, the effects of different peripheral benzodiazapine receptor ligands: PK 11195 [1-(2-chloro-phenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide], Ro5-4864 [7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one] and the newly described SSR 180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridozine[4,5-b] indole-1-acetamide) were analysed on the progression and severity of rheumatoid arthritis in vivo in the Mrl/lpr mice model, following chronic treatment (at 3 mg/kg, i.p. for 30 days). We found that peripheral benzodiazepine receptor ligands have significant beneficial therapeutic action on the development of spontaneous rheumatoid arthritis-like signs. Concomitantly, we mapped immunoreactive peripheral benzodiazepine receptor in inflamed tissues, and we observed that in addition to the infiltrated leukocytes, peripheral benzodiazepine receptor was expressed in synovial membranes, at the cartilage pannus junction and in chondrocytes. Interestingly, we observed that peripheral benzodiazepine receptor expression in chondrocytes was reduced when Mrl/lpr mice developed the pathology and restored upon peripheral benzodiazepine receptor ligand treatment. Altogether, our data provide further evidence of a role played by peripheral benzodiazepine receptor in the regulation of inflammation processes and support new therapeutic applications for specific potent peripheral benzodiazepine receptor ligands.
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D001570:Benzodiazepinones / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058787:GABA-A Receptor Antagonists; D006614:Hindlimb / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007596:Joints / Q000473:pathology; D008024:Ligands; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018613:Microscopy, Confocal; D011963:Receptors, GABA-A / Q000502:physiology*; D013583:Synovial Membrane / Q000473:pathology
D000081:Acetamides; D019138:Antibodies, Blocking; D018501:Antirheumatic Agents; D001570:Benzodiazepinones; D058787:GABA-A Receptor Antagonists; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; C456740:SSR180575; C028513:4'-chlorodiazepam; D008727:Methotrexate; C037850:PK 11195