Immune system to brain signaling: Neuropsychophamacological implications

Laboratory of Nutrition and Integrative Neurobiology, NutriNeuro, INRA UMR 1286, University Victor Segalen Bordeaux 2, Bordeaux, France.
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 02/2011; 130(2):226-38. DOI: 10.1016/j.pharmthera.2011.01.014
Source: PubMed

ABSTRACT There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.

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Available from: Andrew H Miller, Dec 22, 2013
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    • "The inflammatory activity has been shown to be associated with cognitive performance in obese women [10]. The role of neuroinflammation and cytokines in mood disorders and cognitive impairment have also been demonstrated by both animal studies [11– 13]) and clinical data [14] [15]. "
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    ABSTRACT: Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid. Copyright © 2015. Published by Elsevier Ltd.
    Cytokine 07/2015; DOI:10.1016/j.cyto.2015.07.010 · 2.87 Impact Factor
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    • "(Neurauteretal.,2008).Cytokine-inducedGTP-CH1activation, classicallyassessedbymeasuringincreasedproduction ofneopterin,isindeedabletoimpairthedopaminergic neurotransmission(FelgerandMiller,2012)whichisknown tobeinvolvedinmooddisordersandcognitivedysfunctions, includinginconditionsofchronicimmunestimulation(Brydon etal.,2008;Capuronetal.,2012).Consistentwiththese findings,reducedBH4levelshavebeenreportedinpatients withpsychiatricdisorders(Hashimotoetal.,1994;Hoekstra etal.,2001).Similarly,increasedbloodneopterinconcentrations correlatewithagreaterincidenceofdepressiveepisodesin patientswithmajordepression(Celiketal.,2010).Interestingly, chroniclow-gradeinflammationthatisclassicallyreportedin elderlypeopleisassociatedwithactivationofbothIDOandGTP- CH1(Oxenkrug,2010;Capuronetal.,2011b).Moreimportantly, theseenzymaticactivationshavebeenshowntoparticipatein thepathophysiologyofneuropsychiatricsymptoms,whose prevalenceisoftenhighinagedpopulation(Oxenkrug, 2010;Capuronetal.,2011b).Ofnote,inadditiontoimpair monoaminergicneurotransmission,bothenzymescontributes toincreaseoxidativestress(FelgerandMiller,2012;Stoneetal., 2012;Campbelletal.,2014).Increasedneopterinlevelshave beenreportedinobeserats(Finkelsteinetal.,1982)andhumans (Ledochowskietal.,1999;Oxenkrugetal.,2011),suggesting thatactivationoftheGTP-CH1enzymebycytokines,andthe consequentalterationsofdopamineneurotransmission,may contributetothedevelopmentofneuropsychiatricsymptoms reportedinobesity.Althoughthisassumptionstillneedstobe confirmed,itisworthmentioningthatalterationsofdopamine function,togetherwithalterationsinbasalganglia/reward circuitryhavebeenreportedinobesepatients(deWeijeretal., 2011;Volkowetal.,2011).Moreover,depressive-likebehavior isassociatedinDIOmicewithalterationsinstriatalcircuitry, supportingarolefordopamine-relateddisruptionsinobesityassociateddepressivesymptoms(SharmaandFulton ,2013). "
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    ABSTRACT: Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.
    Frontiers in Neuroscience 07/2015; 9:229. DOI:10.3389/fnins.2015.00229 · 3.70 Impact Factor
    • "Furthermore, chronic inflammation is often associated with clinical depression (Miller et al., 2009). Chronic inflammation and oxidative stress have been implicated in the pathophysiology of MDD (Berk et al., 2011; Capuron & Miller, 2011). "
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    ABSTRACT: Context: Silymarin (SM) is extracted from milk thistle Silybum marianum L. (S. marianum) and known for antioxidative and anti-inflammatory effects. Objective: In this study, the potential antidepressant-like effect of acute SM and possible involvement of nitric oxide (NO) were determined in male mice. Material and methods: SM was administered orally (5, 10, 20, 50, 100, 200 mg/kg; p.o.), 60 min before the tests. After assessment of locomotor activity, the immobility time was measured in forced swimming test (FST) and tail suspension test (TST). To assess the possible involvement of NO, a non-specific NO synthase inhibitor, L-NAME (10 mg/kg, i.p.); and a specific iNOS inhibitor, aminoguanidine (AG) (50 mg/kg, i.p.), were administered separately, 30 min before SM (20, 100 mg/kg). Results: SM at its effective doses 10, 20, 50 and 100 mg/kg decreased the immobility time in a dose-dependent manner (P<0.01, P<0.05, P<0.05, P<0.001, respectively) in FST. SM (10, 20, 50 and 100 mg/kg) also lowered the immobility measure dose-dependently in TST (P<0.01, P<0.05, P<0.01, P<0.001, respectively). In addition, 50% of maximum response (ED50) of SM was around 10 mg/kg. The dose 100 mg/kg proved the most effective dose in both the tests. Further, this effect was not related to changes in locomotor activity. Moreover, L-NAME reversed the effect of SM (20, 100 mg/kg) in FST and SM (100 mg/kg) in TST. However, AG did not influence this impact. Conclusion: The antidepressant-like effect of SM is probably mediated at least in part through NO and SM may increase NO tune.
    Pharmaceutical Biology 05/2015; 53(5). DOI:10.3109/13880209.2014.942787 · 1.34 Impact Factor
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