title: Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice.
abstract: Exogenous administration of insulin-like growth factor (IGF)-I has anti-depressant properties in rodent models of depression. However, nothing is known about the anti-depressant properties of IGF-I during inflammation, nor have mechanisms by which IGF-I alters behavior following activation of the innate immune system been clarified. We hypothesized that central IGF-I would diminish depressive-like behavior on a background of an inflammatory response and that it would do so by inducing expression of the brain-derived neurotrophic factor (BDNF) while decreasing pro-inflammatory cytokine expression in the brain. IGF-I (1,000 ng) was administered intracerebroventricularly (i.c.v.) to CD-1 mice. Mice were subsequently given lipopolysaccharide i.c.v. (LPS, 10 ng). Sickness and depressive-like behaviors were assessed followed by analysis of brain steady state mRNA expression. Central LPS elicited typical transient signs of sickness of mice, including body weight loss, reduced feed intake and decreased social exploration toward a novel juvenile. Similarly, LPS increased time of immobility in the tail suspension test (TST). Pretreatment with IGF-I or antidepressants significantly decreased duration of immobility in the TST in both the absence and presence of LPS. To elucidate the mechanisms underlying the anti-depressant action of IGF-I, we quantified steady-state mRNA expression of inflammatory mediators in whole brain using real-time RT-PCR. LPS increased, whereas IGF-I decreased, expression of inflammatory markers interleukin-1ß (IL-1ß), tumor necrosis factor-(TNF)α, inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP). Moreover, IGF-I increased expression of BDNF. These results indicate that IGF-I down regulates glial activation and induces expression of an endogenous growth factor that shares anti-depressant activity. These actions of IGF-I parallel its ability to diminish depressive-like behavior.
authors.affiliation: Integrated Immunology and Behavior Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801-3873, USA.
authors.forename: Sook-Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Robert
authors.initials: R
authors.lastname: Dantzer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Kelley
authors.forename: Robert H
authors.initials: RH
authors.lastname: McCusker
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000276:immunology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003863:Depression / Q000188:drug therapy* / Q000276:immunology; D004435:Eating / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009483:Neuropsychological Tests; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2