Cobalt(II) β-ketoaminato complexes as novel inhibitors of neuroinflammation
2012
Madeira, Jocelyn M. | Beloukhina, Natalia | Boudreau, Kalun | Boettcher, Tyson A. | Gurley, Lydia | Walker, Douglas G. | McNeil, W Stephen | Klegeris, Andis
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 CF₃ 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, L³Co at concentrations (1–10μM) 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 L³Co 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. L³Co 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. L³Co 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 (50μM), but L²Co was highly toxic to all cell types used. Select Co complexes, such as L³Co, may exhibit pharmacological properties beneficial in human diseases involving neuroinflammatory processes. Further studies of the in vivo efficacy, safety and pharmacokinetics of L³Co are warranted.
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