title: Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine.
abstract: Growing evidence suggests that the activation of the inflammatory/immune system contributes to depression pathogenesis, a hypothesis that might hold strong clinical implication. Indeed more than 30% of depressed patients fail to achieve remission, which poses the necessity to identify systems that may represent novel targets for medications. Accordingly, goal of this study was to evaluate the ability of the antidepressant agomelatine to modulate specific components of the immune response in the rat brain following an inflammatory challenge with lipopolysaccharide (LPS). To this aim, adult male rats were chronically treated with agomelatine before being acutely challenged with LPS 16 h after the last drug administration. Rats were sacrificed 2, 6, or 24h after the challenge and several components of the inflammatory response have been investigated by using real-time PCR or ELISA. We found that agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines interleukin-1β and interleukin-6 in the rat brain as well as at peripheral level. At central level, these effects are associated to the inhibition of NF-κB translocation as well as to alterations of mechanisms responsible for microglia activation. In addition, we found that agomelatine was also able to alter the expression of enzymes related to the kynurenine pathway that are thought to represent important mediators to inflammation-related depression. These data disclose novel properties that may contribute to the therapeutic effect of agomelatine providing evidence for a crucial role of specific components of the immune/inflammatory system in the antidepressant response and thereby in depression etiopathology.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Molteni
authors.forename: Flavia
authors.initials: F
authors.lastname: Macchi
authors.forename: Claudia
authors.initials: C
authors.lastname: Zecchillo
authors.forename: Mario
authors.initials: M
authors.lastname: Dell'agli
authors.forename: Elisa
authors.initials: E
authors.lastname: Colombo
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Guidotti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000637:Transaminases / Q000378:metabolism; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D050601:Kynurenine 3-Monooxygenase; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000637:Transaminases; C084711:agomelatine; D009281:Naphthalenes; C021481:kynurenine-oxoglutarate transaminase
keywords: Depression; Gene expression; Hippocampus; Lipopolysaccharide; Microglia; Tryptophan catabolism