title: Cobalt(II) β-ketoaminato complexes as novel inhibitors of neuroinflammation.
abstract: Neuroinflammation contributes to the pathogenesis of neurological disorders including stroke, head trauma, multiple sclerosis, amyotrophic lateral sclerosis as well as age-associated neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Therefore, anti-inflammatory drugs could be used to slow the progression of these diseases. We studied the anti-neuroinflammatory activity of four novel square planar cobalt(II) compounds bearing tetradentate β-ketoaminato ligands with variation in the number of CF(3) ligand substituents, as well as their corresponding unmetallated organic ligands. Cobalt (Co) complexes were consistently more active than their corresponding ligands. One of the complexes, L(3)Co at concentrations (1-10 μM) that were not toxic to cells, significantly reduced cytotoxic secretions by human monocytic THP-1 cells, astrocytoma U-373 MG cells, and primary human microglia. This anti-neurotoxic action of L(3)Co was reduced by SP600125 and PD98059, selective inhibitors of c-Jun NH2-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) kinase (MEK)1/2 respectively. L(3)Co had no effect on secretion of monocyte chemotactic protein-1 (MCP-1) by THP-1 cells, but it inhibited the NADPH oxidase-dependent respiratory burst activity of differentiated human HL-60 cells. L(3)Co upregulated heme oxygenase-1 (HOX-1) expression by THP-1 cells, which may be one of the molecular mechanisms responsible for its anti-inflammatory properties. Two of the Co compounds tested showed activity only at high concentrations (50 μM), but L(2)Co was highly toxic to all cell types used. Select Co complexes, such as L(3)Co, may exhibit pharmacological properties beneficial in human diseases involving neuroinflammatory processes. Further studies of the in vivo efficacy, safety and pharmacokinetics of L(3)Co are warranted.
authors.affiliation: Department of Biology, University of British Columbia Okanagan, Kelowna, BC, Canada.
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Madeira
authors.forename: Natalia
authors.initials: N
authors.lastname: Beloukhina
authors.forename: Kalun
authors.initials: K
authors.lastname: Boudreau
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Boettcher
authors.forename: Lydia
authors.initials: L
authors.lastname: Gurley
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.forename: W Stephen
authors.initials: WS
authors.lastname: McNeil
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
mesh_terms: D000588:Amines / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018922:HL-60 Cells; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D017628:Microglia / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D008024:Ligands; D009942:Organometallic Compounds; D003035:Cobalt; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases