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.
Highlights
Recent studies have unequivocally linked activation of the innate immune system with development of metabolic, subjective and behavioral components of sickness
The increased immobility that occurs 9 h after LPS administration was inhibited by fluoxetine, a classic selective serotonin reuptake inhibitor (SSRI) anti-depressant, and desipramine, a classic tricyclic anti-depressant, (Figure 1B, p < 0.05 for the main effect of LPS, p < 0.05 for the main effect of antidepressants) supporting this behavioral change after LPS as a depressive-like response
The anti-depressant effect of desipramine mimicked that of insulin-like growth factor (IGF)-I, whereas, fluoxetine did not affect immobility in control mice
Summary
Recent studies have unequivocally linked activation of the innate immune system with development of metabolic, subjective and behavioral components of sickness. A similar reduction in mood occurs in humans injected with a typhoid vaccine, and this decline significantly correlates with an increase in IL-6 secretion and enhanced activity within subgenual anterior cingulate cortex [10]. These findings provide a direct cause-effect relationship between neuroinflammation and depression and a distinction between overt sickness and depression. LPS induces transient sickness followed by depressive-like behavior, increased immobility in the forced swim test (FST) and the TST These behaviors are reversed by anti-depressants and by minocycline which attenuates neuroinflammation [11,12]. These and other studies clearly suggest that development of anti-inflammatory regimes would be a viable strategy as a potential therapeutic for inflammation-associated depressive disorders
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
