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Robert Dantzer - One of the best experts on this subject based on the ideXlab platform.
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Effects of voluntary wheel running on LPS-induced Sickness Behavior in aged mice.
Brain behavior and immunity, 2012Co-Authors: Stephen A. Martin, Robert Dantzer, Keith W Kelley, S.j. Johnson, Ryan M. Greene, Brandt D. Pence, J.a. WoodsAbstract:Abstract Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged Sickness Behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and Sickness in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced Sickness Behavior and proinflammatory cytokine gene expression in ∼22-month-old C57BL/6 J mice. Mice were housed with a running wheel (VWR), locked-wheel (Locked), or no wheel (Standard) for 10 weeks, after which they were intraperitoneally injected with LPS across a range of doses (0.02, 0.08, 0.16, 0.33 mg/kg). VWR mice ran on average 3.5 km/day and lost significantly more body weight and body fat, and increased their forced exercise tolerance compared to Locked and Shoebox mice. VWR had no effect on LPS-induced anorexia, adipsia, weight-loss, or reductions in locomotor activity at any LPS dose when compared to Locked and Shoebox groups. LPS induced Sickness Behavior in a dose-dependent fashion (0.33 > 0.02 mg/kg). Twenty-four hours post-injection (0.33 mg/kg LPS or Saline) we found a LPS-induced upregulation of whole brain TNFα, IL-1β, and IL-10 mRNA, and increased IL-1β and IL-6 in the spleen and liver; these effects were not attenuated by VWR. We conclude that VWR does not reduce LPS-induced exaggerated or prolonged Sickness Behavior in aged animals, or 24 h post-injection (0.33 mg/kg LPS or Saline) brain and peripheral proinflammatory cytokine gene expression. The necessity of the Sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.
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132. The effects of voluntary-wheel exercise on LPS-induced Sickness Behavior in aged mice
Brain Behavior and Immunity, 2012Co-Authors: Stephen A. Martin, Robert Dantzer, Keith W Kelley, S.j. Johnson, Ryan M. Greene, J.a. WoodsAbstract:Introduction: Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged Sickness Behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and Sickness Behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running (VWR) would attenuate LPS-induced Sickness Behavior in aged mice. Methods: Male 22 month-old C57BL/6 J mice were randomized to voluntary-wheel running, locked-wheel, or shoebox cage intervention for 10 weeks. Following the intervention, mice were i.p. injected with one of three LPS doses (0.33 mg/kg, 0.16 mg/kg, 0.08 mg/kg) or saline, and Sickness Behavior was assessed by weight-loss, food intake, and fluid intake. Results: VWR had no effect on weight-loss, food intake, or fluid intake. There was a dose-dependent response for food and fluid intake, in that the 0.33 mg/kg LPS dose induced the greatest reductions in food and fluid intake. This corresponded with a tendency for prolonged weight loss in the 0.33 mg/kg LPS mice. Conclusions: VWR does not reduce prolonged or exaggerated LPS-induced Sickness Behavior in aged mice. The necessity of the Sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.
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Cytokine, Sickness Behavior, and Depression
Immunology and Allergy Clinics of North America, 2009Co-Authors: Robert DantzerAbstract:The psychologic and Behavioral components of Sickness represent, together with fever response and associated neuroendocrine changes, a highly organized strategy of the organism to fight infection. This strategy, referred to as Sickness Behavior, is triggered by the proinflammatory cytokines produced by activated cells of the innate immune system in contact with specific pathogen-associated molecular patterns (PAMPs). Interleukin-1 and other cytokines act on the brain via (1) a neural route represented by the primary afferent neurons that innervate the body site where the infectious process takes place and (2) a humoral pathway that involves the production of proinflammatory cytokines. This article presents the current knowledge on the way this communication system is organized and regulated and the implications of these advances for understanding brain physiology and pathology.
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The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced Sickness Behavior.
Psychopharmacology, 2009Co-Authors: Karine Palin, Robert Dantzer, Rose-marie Bluthé, Robert Mccusker, Thierry Levade, Françoise Moos, Keith KelleyAbstract:RATIONALE: During the course of an infection, the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) acts in the brain to trigger development of Behavioral responses, collectively termed Sickness Behavior. Biological activities of TNFalpha can be mediated by TNF receptor type 1 (TNF-R1) and type 2 (TNF-R2). TNFalpha activates neutral sphingomyelinase through the TNF-R1 adapter protein FAN (factor associated with neutral sphingomyelinase activation), but a Behavioral role of FAN in the brain has never been reported. OBJECTIVES: We hypothesized that TNFalpha-induced Sickness Behavior requires TNF-R1 and that FAN is a necessary component for this response. MATERIALS AND METHODS: We determined the role of brain TNF-R1 in Sickness Behavior by administering an optimal amount of TNFalpha intracerebroventricularly (i.c.v., 50 ng/mouse) to wild-type (WT), TNF-R1-, TNF-R2-, and FAN-deficient mice. Sickness was assessed by decreased social exploration of a novel juvenile, induction of immobility, and loss of body weight. RESULTS: TNF-R1-deficient mice were resistant to the Sickness-inducing properties of i.c.v. TNFalpha, whereas both TNF-R2-deficient and WT mice were fully responsive. Furthermore, the complete absence of TNFalpha-induced Sickness Behavior in FAN-deficient mice provided in vivo evidence that FAN-dependent TNF-R1 signaling is critical for this central action of TNFalpha. CONCLUSIONS: This is the first report to demonstrate that TNFalpha-induced Sickness Behavior is fully mediated by TNF-R1 and that the adaptor protein FAN is a necessary intracellular intermediate for Sickness Behavior.
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exaggerated Sickness Behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide
Neurobiology of Aging, 2008Co-Authors: Yan Huang, Robert Dantzer, Rodney W. Johnson, Christopher J Henry, Jonathan P. GodboutAbstract:Age-associated changes in glial reactivity may predispose individuals to exacerbated neuroinflammatory cytokine responses that are permissive to cognitive and Behavioral complications. The purpose of this study was to determine if aging is associated with an exaggerated Sickness response to central innate immune activation. Our results show that intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) caused a heightened proinflammatory cytokine response (IL-1beta, IL-6, and TNFalpha) in the cerebellum 2h post i.c.v. injection in aged mice compared to adults. This amplified inflammatory profile was consistent with a brain region-dependent increase in reactive glial markers (MHC class II, TLR2 and TLR4). Moreover, LPS caused a prolonged Sickness Behavior response in aged mice that was paralleled by a protracted expression of brain cytokines in the cerebellum and hippocampus. Finally, central LPS injection caused amplified and prolonged IL-6 levels at the periphery of aged mice. Collectively, these data establish that activation of the central innate immune system leads to exacerbated neuroinflammation and prolonged Sickness Behavior in aged as compared to adult mice.
Keith W Kelley - One of the best experts on this subject based on the ideXlab platform.
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Effects of voluntary wheel running on LPS-induced Sickness Behavior in aged mice.
Brain behavior and immunity, 2012Co-Authors: Stephen A. Martin, Robert Dantzer, Keith W Kelley, S.j. Johnson, Ryan M. Greene, Brandt D. Pence, J.a. WoodsAbstract:Abstract Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged Sickness Behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and Sickness in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced Sickness Behavior and proinflammatory cytokine gene expression in ∼22-month-old C57BL/6 J mice. Mice were housed with a running wheel (VWR), locked-wheel (Locked), or no wheel (Standard) for 10 weeks, after which they were intraperitoneally injected with LPS across a range of doses (0.02, 0.08, 0.16, 0.33 mg/kg). VWR mice ran on average 3.5 km/day and lost significantly more body weight and body fat, and increased their forced exercise tolerance compared to Locked and Shoebox mice. VWR had no effect on LPS-induced anorexia, adipsia, weight-loss, or reductions in locomotor activity at any LPS dose when compared to Locked and Shoebox groups. LPS induced Sickness Behavior in a dose-dependent fashion (0.33 > 0.02 mg/kg). Twenty-four hours post-injection (0.33 mg/kg LPS or Saline) we found a LPS-induced upregulation of whole brain TNFα, IL-1β, and IL-10 mRNA, and increased IL-1β and IL-6 in the spleen and liver; these effects were not attenuated by VWR. We conclude that VWR does not reduce LPS-induced exaggerated or prolonged Sickness Behavior in aged animals, or 24 h post-injection (0.33 mg/kg LPS or Saline) brain and peripheral proinflammatory cytokine gene expression. The necessity of the Sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.
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132. The effects of voluntary-wheel exercise on LPS-induced Sickness Behavior in aged mice
Brain Behavior and Immunity, 2012Co-Authors: Stephen A. Martin, Robert Dantzer, Keith W Kelley, S.j. Johnson, Ryan M. Greene, J.a. WoodsAbstract:Introduction: Peripheral stimulation of the innate immune system with LPS causes exaggerated neuroinflammation and prolonged Sickness Behavior in aged mice. Regular moderate intensity exercise has been shown to exert anti-inflammatory effects that may protect against inappropriate neuroinflammation and Sickness Behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running (VWR) would attenuate LPS-induced Sickness Behavior in aged mice. Methods: Male 22 month-old C57BL/6 J mice were randomized to voluntary-wheel running, locked-wheel, or shoebox cage intervention for 10 weeks. Following the intervention, mice were i.p. injected with one of three LPS doses (0.33 mg/kg, 0.16 mg/kg, 0.08 mg/kg) or saline, and Sickness Behavior was assessed by weight-loss, food intake, and fluid intake. Results: VWR had no effect on weight-loss, food intake, or fluid intake. There was a dose-dependent response for food and fluid intake, in that the 0.33 mg/kg LPS dose induced the greatest reductions in food and fluid intake. This corresponded with a tendency for prolonged weight loss in the 0.33 mg/kg LPS mice. Conclusions: VWR does not reduce prolonged or exaggerated LPS-induced Sickness Behavior in aged mice. The necessity of the Sickness response is critical for survival and may outweigh the subtle benefits of exercise training in aged animals.
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tumor necrosis factor α induced Sickness Behavior is impaired by central administration of an inhibitor of c jun n terminal kinase
Psychopharmacology, 2008Co-Authors: K Palin, Robert Dantzer, Keith W Kelley, Françoise Moos, R.h. Mccusker, K. StrleAbstract:Rationale Tumor necrosis factor-α (TNFα) acts within the brain to induce Sickness Behavior, but the molecular mechanisms are still unknown. TNFα binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.
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Tumor necrosis factor-α-induced Sickness Behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase
Psychopharmacology, 2008Co-Authors: Karine Palin, Robert Dantzer, Françoise Moos, R.h. Mccusker, K. Strle, Keith W KelleyAbstract:Rationale Tumor necrosis factor-α (TNFα) acts within the brain to induce Sickness Behavior, but the molecular mechanisms are still unknown. TNFα binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors. Objectives We hypothesized that TNFα-induced Sickness Behavior can be blocked by a novel JNK inhibitor. Methods To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFα (50 ng/mouse) to induce Sickness Behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight. Results Pre-treatment with D-JNKI-1 (10 ng/mouse), but not D-TAT, significantly inhibited all three indices of Sickness induced by central TNFα. Conclusions These findings demonstrate that D-JNKI-1 can abrogate TNFα-induced Sickness Behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced Sickness Behavior.
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Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of Sickness Behavior followed by chronic depressive-like Behavior
Brain Behavior and Immunity, 2008Co-Authors: Maite Moreau, Robert Dantzer, Keith W Kelley, Jason C. O'connor, J.a. Woods, Caroline Andre, Sara A. Dumich, Jacques Lestage, Nathalie CastanonAbstract:Although cytokine-induced Sickness Behavior is now well-established, the mechanisms by which chronic inflammation and depression are linked still remain elusive. Therefore this study aimed to develop a suitable model to identify the neurobiological basis of depressive-like Behavior induced by chronic inflammation, independently of Sickness Behavior. We chose to measure the Behavioral consequences of chronic inoculation of mice with Bacillus Calmette-Guerin (BCG), which has been shown to chronically activate both lung and brain indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates the occurrence of depressive-like Behavior following acute innate immune system activation. BCG inoculation induced an acute episode of Sickness (approximately 5 days) that was followed by development of delayed depressive-like Behaviors lasting over several weeks. Transient body weight loss, reduction of motor activity and the febrile response to BCG were dissociated temporarily from a sustained increase in the duration of immobility in both forced swim and tail suspension tests, reduced voluntary wheel running and decreased preference for sucrose (a test of anhedonia). Moreover, we show that a distinct pattern of cytokine production and IDO activation parallels the transition from Sickness to depression. Protracted depressive-like Behavior, but not Sickness Behavior, was associated with sustained increase in plasma interferon-γ and TNF-α concentrations and peripheral IDO activation. Together, these promising new data establish BCG inoculation of mice as a reliable rodent model of chronic inflammation-induced depressive-like Behaviors that recapitulate many clinical observations and provide important clues about the neurobiological basis through which cytokines may have an impact on affective Behaviors.
Rodney W. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of DNA Methylation With Zebularine Alters Lipopolysaccharide-Induced Sickness Behavior and Neuroinflammation in Mice.
Frontiers in neuroscience, 2018Co-Authors: Stephanie M. Matt, Jalisa D. Zimmerman, Marcus A. Lawson, Angela C. Bustamante, Monica Uddin, Rodney W. JohnsonAbstract:Activity of DNA methyltransferases (DNMTs), the enzymes that catalyze DNA methylation, is dynamically regulated in the brain. DNMT inhibitors alter DNA methylation globally in the brain and at individual neural plasticity-associated genes, but how DNMT inhibitors centrally influence lipopolysaccharide (LPS)-induced neuroinflammation is not known. We investigated whether the DMNT inhibitor, zebularine, would alter Sickness Behavior, DNA methylation of the Il-1β promoter and expression of inflammatory genes in hippocampus and microglia. Contrary to our hypothesis that zebularine may exaggerate LPS-induced Sickness response and neuroinflammation, adult mice treated with an intracerebroventricular (ICV) injection of zebularine prior to LPS had surprisingly faster recovery of burrowing Behavior compared to mice treated with LPS. Further, genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were differentially expressed by zebularine alone or in combination with LPS. Bisulfite pyrosequencing revealed that ICV zebularine led to decreased DNA methylation of two CpG sites near the Il-1β proximal promoter alone or in combination with LPS. Zebularine treated mice still exhibited decreased DNA methylation 48 h after treatment when LPS-induced Sickness Behavior as well as hippocampal and microglial gene expression were similar to control mice. Taken together, these data suggest that decreased DNA methylation, specifically of the Il-1β promoter region, with a DNMT inhibitor in the brain disrupts molecular mechanisms of neuroinflammation.
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Central inhibition of DNA methylation improves lipopolysaccharide-induced Sickness Behavior in mice
Brain Behavior and Immunity, 2017Co-Authors: Jalisa D. Zimmerman, Stephanie M. Matt, Marcus A. Lawson, Rodney W. JohnsonAbstract:DNA methyltransferases (DNMTs) regulate gene expression by catalyzing DNA methylation but their role in the brain in regulating Sickness Behavior induced by neuroinflammation is not known. Therefore, we sought to determine the central effects of demethylation of DNA with a DMNT inhibitor on Sickness Behavior induced by lipopolysaccharide (LPS). Adult C57 BL/6J mice (age 3–6 months) were implanted with an intracerebroventricular (ICV) cannula, and after 7 days of recovery were injected ICV with saline vehicle or the DMNT inhibitor zebularine (300 ng/μl). Saline vehicle or LPS (10 ng/μl) was injected ICV 30 min later. Burrowing Behavior and body weight were measured at 4, 8, 12, 24, and 48 h to assess Sickness Behavior. LPS reduced burrowing Behavior in mice (p
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Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced Sickness Behavior.
Journal of neuroinflammation, 2011Co-Authors: Michael D. Burton, Nathan L. Sparkman, Rodney W. JohnsonAbstract:Background Interleukin (IL)-6 is produced in the brain during peripheral infection and plays an important but poorly understood role in Sickness Behavior. Therefore, this study investigated the capacity of soluble gp130 (sgp130), a natural inhibitor of the IL-6 trans-signaling pathway to regulate IL-6 production in microglia and neurons in vitro and its effects on lipopolysaccharide (LPS)-induced Sickness Behavior in vivo.
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Central inhibition of interleukin-1β ameliorates Sickness Behavior in aged mice
Brain behavior and immunity, 2008Co-Authors: J. Abraham, Rodney W. JohnsonAbstract:In elderly individuals high levels of interleukin-1beta (IL-1beta) in the brain have been implicated in infection-related Behavioral pathologies but this has not been directly tested. Therefore, the current study investigated if Sickness Behavior in aged animals elicited by peripheral injection of lipopolysaccharide (LPS) is mediated through central IL-1beta. Adult and aged mice were injected intracerebroventricularly with either saline or IL-1ra (4mug) immediately prior to intraperitoneal administration of saline or LPS (10mug) and locomotor and social Behaviors were assessed. As anticipated, LPS depressed locomotor activity and social Behavior in both adult and aged mice but the Behavioral deficits were markedly greater in the aged at 24h. Pretreatment with IL-1ra did not affect LPS-induced Sickness Behavior in adults; however, in aged mice IL-1ra attenuated LPS-induced Sickness Behavior, restoring it to the level exhibited by young adults. Twenty-four hours post-injection hippocampal and hypothalamic tissues were collected to determine IL-1beta mRNA expression. Neither LPS nor IL-1ra affected IL-1beta mRNA levels in adults, presumably because any effect of LPS had dissipated by 24h. In contrast, IL-1beta mRNA was markedly higher in aged mice 24h after LPS, and prior treatment with IL-1ra either blocked or attenuated this effect in the hippocampus and hypothalamus, respectively. Taken together these data provide the first direct evidence that central IL-1beta is responsible for the severe Sickness Behavior observed in aged animals after LPS treatment. Thus, inhibiting the central actions of IL-1beta may be useful for minimizing Behavioral complications in older individuals with an infection.
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exaggerated Sickness Behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide
Neurobiology of Aging, 2008Co-Authors: Yan Huang, Robert Dantzer, Rodney W. Johnson, Christopher J Henry, Jonathan P. GodboutAbstract:Age-associated changes in glial reactivity may predispose individuals to exacerbated neuroinflammatory cytokine responses that are permissive to cognitive and Behavioral complications. The purpose of this study was to determine if aging is associated with an exaggerated Sickness response to central innate immune activation. Our results show that intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) caused a heightened proinflammatory cytokine response (IL-1beta, IL-6, and TNFalpha) in the cerebellum 2h post i.c.v. injection in aged mice compared to adults. This amplified inflammatory profile was consistent with a brain region-dependent increase in reactive glial markers (MHC class II, TLR2 and TLR4). Moreover, LPS caused a prolonged Sickness Behavior response in aged mice that was paralleled by a protracted expression of brain cytokines in the cerebellum and hippocampus. Finally, central LPS injection caused amplified and prolonged IL-6 levels at the periphery of aged mice. Collectively, these data establish that activation of the central innate immune system leads to exacerbated neuroinflammation and prolonged Sickness Behavior in aged as compared to adult mice.
Maria Martha Bernardi - One of the best experts on this subject based on the ideXlab platform.
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Zinc, but not paracetamol, prevents depressive-like Behavior and Sickness Behavior, and inhibits interferon-gamma and astrogliosis in rats.
Brain behavior and immunity, 2020Co-Authors: Thiago Berti Kirsten, Marcella C Galvao, Danilo Cabral, Eduardo Fernandes Bondan, Renan Monteiro, Maria Martha BernardiAbstract:Abstract Considering all mental and addictive disorders, depression is the most responsible for years of life lost due to premature mortality and disability. Antidepressant drugs have limited effectiveness. Depression can be triggered by immune/inflammatory factors. Zinc and paracetamol interfere with immune system and have demonstrated beneficial effects on depression treatment when administered concomitant with antidepressant drugs. The objective of this study was to test zinc and/or paracetamol as treatments of depressive-like Behavior, Sickness Behavior, and anxiety in rats, as well as to understand the central and peripheral mechanisms involved. Sickness Behavior and depressive-like Behavior were induced in rats with repetitive lipopolysaccharide (LPS, 1 mg/kg for two consecutive days) administrations. Rats received zinc and/or paracetamol for three consecutive days. Sickness Behavior (daily body weight and open field general activity); anxiety (light-dark test); depressive-like/antidepressant Behavior (forced swim test); plasma corticosterone and interferon (IFN)-gamma levels; and glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH) brain expression were evaluated. LPS induced Sickness Behavior and depressive-like Behavior, as well as elevated IFN-gamma levels and increased GFAP expression. Zinc prevented both Behavioral and biochemical impairments. Paracetamol and zinc + paracetamol association induced only slight beneficial effects. Anxiety, corticosterone, and TH do not seem be related with depression and the other Behavioral and neuroimmune changes. In conclusion, zinc treatment was beneficial for Sickness Behavior and depressive-like Behavior without concomitant administration of antidepressants. IFN-gamma and GFAP were linked with the expression of Sickness Behavior and depressive-like Behavior and were also involved with the antidepressant effects. Therefore, zinc, IFN-gamma, and GFAP pathways should be considered for depression treatment.
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Abstract # 2063 Paradoxical selenium effect induced by stress on LPS-induced Sickness Behavior in rats
Brain Behavior and Immunity, 2019Co-Authors: T.r. Mazuco, Maria Martha Bernardi, E.p. Silva, T.f. Biondi, L.v. Bonamin, Thiago Berti KirstenAbstract:Sickness Behavior is a motivational state that can be modulated by the environmental context. We induced Sickness Behavior in rats using lipopolysaccharides (LPS). Rats were treated with selenium in order to verify possible changes of Sickness Behavior expression. We exposed these rats to a restraint stress challenge and studied the paradigms: cure of the organism x preservation of the species x fight or flight. Studies of open-field Behaviors, IL-1 beta and IFN-gamma serum levels, necropsy and histology were performed. LPS induced Sickness Behavior was evidenced by decreased motor/exploratory activity and increased proinflammatory immune mediators’ levels. Selenium supplementation did not exert beneficial effects on the Sickness Behavior symptoms. Therefore, selenium deficiency does not seem to be related to Sickness Behavior expression. LPS exposure did not affect Behavior of rats in presence of stress. Thereby, Sickness Behavior was abrogated during stressor events to prioritize survival Behaviors, such as fight or flight. Contrarily, the association of LPS, selenium, and stress induced Sickness Behavior even during stressor events and caused death of more than half rats of this experimental group. Necropsy revealed diffuse vascular damages in adrenals, liver, brain, and especially in the lungs. Adult respiratory distress syndrome secondary to circulatory shock was the cause-mortis. Thus, a paradox was seen in relation to selenium: instead of protection, it was toxic to rats that received LPS and stress. CAPES/Premio.
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propentofylline prevents Sickness Behavior and depressive like Behavior induced by lipopolysaccharide in rats via neuroinflammatory pathway
PLOS ONE, 2017Co-Authors: Marcia Maria Tivelli Moraes, Marcella C Galvao, Danilo Cabral, Cideli De Paula Coelho, Nicolle Queirozhazarbassanov, Maria Marlene Martins, Eduardo Fernandes Bondan, Maria Martha Bernardi, Thiago Berti KirstenAbstract:Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied Sickness Behavior, by assessing daily body weight, open field Behavior, and TNF-α plasmatic levels. Anxiety-like Behavior (light-dark test), depressive-like Behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field Behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced Sickness Behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like Behavior in rats. Propentofylline prevented Sickness Behavior after four days of consecutive treatment, as well as prevented the depressive-like Behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced Sickness Behavior and depressive-like Behavior in rats. Propentofylline prevented both Sickness Behavior and depressive-like Behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.
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Zinc Prevents Sickness Behavior Induced by Lipopolysaccharides after a Stress Challenge in Rats
PloS one, 2015Co-Authors: Thiago Berti Kirsten, Marcella C Galvao, Thiago Marinho Reis-silva, Nicolle Queiroz-hazarbassanov, Maria Martha BernardiAbstract:Sickness Behavior is considered part of the specific beneficial adaptive Behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, Sickness Behavior should be momentarily abrogated to prioritize survival Behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced Sickness Behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the Sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field Behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced Sickness Behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent Sickness Behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor Behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.
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Temporal Analysis of Lipopolysaccharide-Induced Sickness Behavior in Virgin and Lactating Female Rats
Neuroimmunomodulation, 2013Co-Authors: Amanda Nascimento, Maria Martha Bernardi, Vanessa Gallego Arias Pecorari, C O Massoco, Luciano Freitas FelícioAbstract:Objectives: Lipopolysaccharide (LPS), an endotoxin that originates from the cell wall of Gram-negative bacteria, activates the immune system to release proinflammatory cytokines and to induce Sickness Behavior. The present study sought to characterize the time-dependent effects of LPS on fever, body weight, and food and water consumption in female virgin and lactating rats exposed to an LPS dose previously reported to induce Sickness Behavior in pregnant female rats. Methods: Virgin female Wistar rats in the estrous phase and lactating female Wistar rats on the third day of lactation received 100 µg/kg LPS or saline solution. Tympanic temperature, body weight, and food and water consumption were assessed 0, 2, 24, 48, 72, 96, and 120 h after treatment. Results: In lactating female rats, tympanic temperature was attenuated compared with virgin females. Food consumption and body weight gain in both groups decreased, but lactating rats consumed more food than virgin rats. Water consumption increased at different time points. Conclusion: LPS exposure induced several signs of Sickness Behavior, including decreases in food consumption and body weight gain, and induced adipsia in both virgin and lactating female rats. Because the time course and profile of fever varied between lactating and nonlactating animals, these responses appeared to depend on the physiological state of female animals.
Thiago Berti Kirsten - One of the best experts on this subject based on the ideXlab platform.
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Zinc, but not paracetamol, prevents depressive-like Behavior and Sickness Behavior, and inhibits interferon-gamma and astrogliosis in rats.
Brain behavior and immunity, 2020Co-Authors: Thiago Berti Kirsten, Marcella C Galvao, Danilo Cabral, Eduardo Fernandes Bondan, Renan Monteiro, Maria Martha BernardiAbstract:Abstract Considering all mental and addictive disorders, depression is the most responsible for years of life lost due to premature mortality and disability. Antidepressant drugs have limited effectiveness. Depression can be triggered by immune/inflammatory factors. Zinc and paracetamol interfere with immune system and have demonstrated beneficial effects on depression treatment when administered concomitant with antidepressant drugs. The objective of this study was to test zinc and/or paracetamol as treatments of depressive-like Behavior, Sickness Behavior, and anxiety in rats, as well as to understand the central and peripheral mechanisms involved. Sickness Behavior and depressive-like Behavior were induced in rats with repetitive lipopolysaccharide (LPS, 1 mg/kg for two consecutive days) administrations. Rats received zinc and/or paracetamol for three consecutive days. Sickness Behavior (daily body weight and open field general activity); anxiety (light-dark test); depressive-like/antidepressant Behavior (forced swim test); plasma corticosterone and interferon (IFN)-gamma levels; and glial fibrillary acidic protein (GFAP) and tyrosine hydroxylase (TH) brain expression were evaluated. LPS induced Sickness Behavior and depressive-like Behavior, as well as elevated IFN-gamma levels and increased GFAP expression. Zinc prevented both Behavioral and biochemical impairments. Paracetamol and zinc + paracetamol association induced only slight beneficial effects. Anxiety, corticosterone, and TH do not seem be related with depression and the other Behavioral and neuroimmune changes. In conclusion, zinc treatment was beneficial for Sickness Behavior and depressive-like Behavior without concomitant administration of antidepressants. IFN-gamma and GFAP were linked with the expression of Sickness Behavior and depressive-like Behavior and were also involved with the antidepressant effects. Therefore, zinc, IFN-gamma, and GFAP pathways should be considered for depression treatment.
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Abstract # 2063 Paradoxical selenium effect induced by stress on LPS-induced Sickness Behavior in rats
Brain Behavior and Immunity, 2019Co-Authors: T.r. Mazuco, Maria Martha Bernardi, E.p. Silva, T.f. Biondi, L.v. Bonamin, Thiago Berti KirstenAbstract:Sickness Behavior is a motivational state that can be modulated by the environmental context. We induced Sickness Behavior in rats using lipopolysaccharides (LPS). Rats were treated with selenium in order to verify possible changes of Sickness Behavior expression. We exposed these rats to a restraint stress challenge and studied the paradigms: cure of the organism x preservation of the species x fight or flight. Studies of open-field Behaviors, IL-1 beta and IFN-gamma serum levels, necropsy and histology were performed. LPS induced Sickness Behavior was evidenced by decreased motor/exploratory activity and increased proinflammatory immune mediators’ levels. Selenium supplementation did not exert beneficial effects on the Sickness Behavior symptoms. Therefore, selenium deficiency does not seem to be related to Sickness Behavior expression. LPS exposure did not affect Behavior of rats in presence of stress. Thereby, Sickness Behavior was abrogated during stressor events to prioritize survival Behaviors, such as fight or flight. Contrarily, the association of LPS, selenium, and stress induced Sickness Behavior even during stressor events and caused death of more than half rats of this experimental group. Necropsy revealed diffuse vascular damages in adrenals, liver, brain, and especially in the lungs. Adult respiratory distress syndrome secondary to circulatory shock was the cause-mortis. Thus, a paradox was seen in relation to selenium: instead of protection, it was toxic to rats that received LPS and stress. CAPES/Premio.
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propentofylline prevents Sickness Behavior and depressive like Behavior induced by lipopolysaccharide in rats via neuroinflammatory pathway
PLOS ONE, 2017Co-Authors: Marcia Maria Tivelli Moraes, Marcella C Galvao, Danilo Cabral, Cideli De Paula Coelho, Nicolle Queirozhazarbassanov, Maria Marlene Martins, Eduardo Fernandes Bondan, Maria Martha Bernardi, Thiago Berti KirstenAbstract:Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied Sickness Behavior, by assessing daily body weight, open field Behavior, and TNF-α plasmatic levels. Anxiety-like Behavior (light-dark test), depressive-like Behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field Behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced Sickness Behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like Behavior in rats. Propentofylline prevented Sickness Behavior after four days of consecutive treatment, as well as prevented the depressive-like Behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced Sickness Behavior and depressive-like Behavior in rats. Propentofylline prevented both Sickness Behavior and depressive-like Behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases.
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Zinc Prevents Sickness Behavior Induced by Lipopolysaccharides after a Stress Challenge in Rats
PloS one, 2015Co-Authors: Thiago Berti Kirsten, Marcella C Galvao, Thiago Marinho Reis-silva, Nicolle Queiroz-hazarbassanov, Maria Martha BernardiAbstract:Sickness Behavior is considered part of the specific beneficial adaptive Behavioral and neuroimmune changes that occur in individuals in response to infectious/inflammatory processes. However, in dangerous and stressful situations, Sickness Behavior should be momentarily abrogated to prioritize survival Behaviors, such as fight or flight. Taking this assumption into account, we experimentally induced Sickness Behavior in rats using lipopolysaccharides (LPS), an endotoxin that mimics infection by gram-negative bacteria, and then exposed these rats to a restraint stress challenge. Zinc has been shown to play a regulatory role in the immune and nervous systems. Therefore, the objective of this study was to examine the effects of zinc treatment on the Sickness response of stress-challenged rats. We evaluated 22-kHz ultrasonic vocalizations, open-field Behavior, tumor necrosis factor α (TNF-α), corticosterone, and brain-derived neurotrophic factor (BDNF) plasma levels. LPS administration induced Sickness Behavior in rats compared to controls, i.e., decreases in the distance traveled, average velocity, rearing frequency, self-grooming, and number of vocalizations, as well as an increase in the plasma levels of TNF-α, compared with controls after a stressor challenge. LPS also decreased BDNF expression but did not influence anxiety parameters. Zinc treatment was able to prevent Sickness Behavior in LPS-exposed rats after the stress challenge, restoring exploratory/motor Behaviors, communication, and TNF-α levels similar to those of the control group. Thus, zinc treatment appears to be beneficial for sick animals when they are facing risky/stressful situations.
