title: A novel carboline derivative inhibits nitric oxide formation in macrophages independent of effects on tumor necrosis factor α and interleukin-1β expression.
abstract: Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. β-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-β-carboline (8-Gly carb) on NO formation and NF-κB activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-L-arginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-κB-mediated gene expression in differentiated THP1-XBlue cells, a human NF-κB reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor α (TNFα)-induced phosphorylation of the p38 mitogen-activated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide- or TNFα-stimulated expression of TNFα and interleukin-1β. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-κB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.) cgrodzki@ucdavis.edu.
authors.forename: Ana Cristina G
authors.initials: AC
authors.lastname: Grodzki
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.).
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Poola
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.).
authors.forename: Nagarekha
authors.identifier: http://orcid.org/0000-0002-0196-1167
authors.initials: N
authors.lastname: Pasupuleti
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.).
authors.forename: Michael H
authors.identifier: http://orcid.org/0000-0003-1301-3399
authors.initials: MH
authors.lastname: Nantz
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.).
authors.forename: Pamela J
authors.identifier: http://orcid.org/0000-0001-7665-7584
authors.initials: PJ
authors.lastname: Lein
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine (A.C.G.G., F.G., P.J.L.), and Department of Neurology, School of Medicine (N.P., F.G.), University of California, Davis, California; and Department of Chemistry, University of Louisville, Louisville, Kentucky (B.P., M.H.N.).
authors.forename: Fredric
authors.initials: F
authors.lastname: Gorin
mesh_terms: D000818:Animals; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D002243:Carbolines; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide