Inhibitory action of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK 11195) on some mononuclear phagocyte functions.
Peripheral benzodiazepine receptors (PBRs) are widely distributed throughout the body, but their functions are unknown. They are found on mononuclear phagocytes, and they are up-regulated in a number of neurological and other disease states. We explored the functional consequences of PBR ligand binding to mononuclear-derived cells using the high-affinity ligands 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK 11195) and 4'-chlorodiazepam (7-chloro-5-(4'-chlorophenyl)-1, 3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one; Ro 5-4864). The functions were the following: respiratory burst; secretion of glutamate, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha); toxicity of culture supernatants towards SH-SY5Y human neuroblastoma cells; and expression of the inflammatory surface markers HLA-DR and Fcgamma RII (CDw32). PK 11195 inhibited the respiratory burst response, reduced release of glutamate and IL-1beta, and suppressed secretion of products cytotoxic to neuronal cells. Selectivity was suggested by the failure of PK 11195 to influence TNF-alpha secretion or expression of HLA-DR and CDw32. Powerful ligands of PBRs, such as PK 11195, may be useful inhibitors of selective macrophage functions, retarding both local and systemic inflammation. Since PK 11195 readily enters the brain, it may be beneficial in treating central as well as peripheral inflammatory diseases.
Klegeris
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Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada. aklegeri@interchange.ubc.ca
McGeer
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McGeer
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D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017452:Receptors, IgG / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D000954:Antigens, Surface; D000970:Antineoplastic Agents; C080571:Fc gamma receptor IIB; D006684:HLA-DR Antigens; D007375:Interleukin-1; D007546:Isoquinolines; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; C037850:PK 11195