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Yanett Roman2/25/09Biol 520
Investigates interaction between behavior and the immune system, mediated by the endocrine system and nervous systemlink between bi-directional communication of the
immune system with the endocrine an nervous system
CNS
Immune system
Nps Hormones
Neurotransmitters
CytokinesNps
Ziemssen & Kern 2007
Ziemssen & Kern 2007
Major depression (clinical depression), and chronic depression, are the most common types of depression
National Institute of Mental Health characterizes major depression by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities
http://www.webmd.com/depressionhttp://www.webmd.com/depression//
Some chronic diseases and cancers are treated by proinflammatory cytokines interferon-α (INF-α) and interferon-γ (INF-γ)Used because of their strong
immunomodulatory and antiviral effects Several neuropsychiatric disorders have
been linked to proinflammatory cytokines INF-α and INF-γDepressionAnxietyPsychosis Cognitive impairment
Myint et al 2008Myint et al 2008
Type IIFN-α is produced by leukocytesMainly involved in innate immune response
against viral infection Type II
IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells
Also known as immune interferonIFN-γ has antiviral, immunoregulatory, and
anti-tumor properties
http://en.wikipedia.org/wiki/Interferon#References
IDO is inducible in different cell typesFibroblastMonocytes
○ Macropages ○ Dendritic cells
INF-γ and INF-α are they key inducers of IDO
IDO catalyzes cleavage of tryptophan (TRP) to form kynurenine (the first rate limiting step in the Kynurenne pathway)Depletion of leads to antimicrobial effects,
depression, T cell proliferation, & neurotoxic metabolites
Kwidzinskinet al 2005Kwidzinskinet al 2005
Tryptophan (TRP) is catabolized in mammals by two enzymesTryptophan 2,3-dioxygenaseIDO
TPH-1 and TPH-2 Can pass Blood brain barrier TRP is the precursor for serotonin
Myint & Schwartz 2009
Oxidative Tryptophan Metabolism along the Kynurenine pathway
Sanni et al1998
Neuro- exitotoxin
Kynurenine (KYN) is able to pass through the blood brain barrier 3-hydroxynurenine leads to the production of
reactive oxygen species that initiate neural apoptosis○ QA
Increased KYN neurotoxic levels have been seen in some neurodegenerative diseasesHuntington's diseaseParkinson's diseaseDepression
IDO induced neurotoxicity and may reduce the production of kynurenine acid (KA)
Wichers et al 2005Wichers et al 2005
KAReduces neurotoxicity since it is an antagonist
of the glutamate recognition site in the N-methyl-D-aspartate (NMDA) receptor
Has been found to be released by astrocytes for neural protection
KA synthesizing enzyme can not compete with the direct pathway of QA
QAAn endogenous excitatory amino acid
neurotransmitterPotent (NMDA) receptor agonist
Sanni et al 2005
Neurotransmitter that is involved in a variety of different physiological functions in both the peripheral and nervous system
Synthesized within the brain from tryptophan
Impaired or altered 5-TH neurotransmitters appear to be a central dysfunction that lead to depression
Activated monocyte
Proinfalmmatory Cytokines IFNγ, IFN α
IDOIDO
KYN
Immune activation
SeratoninSeratonin
5-hydroxyltrytophan
KAKA
Kynurenine aminotransferase
neuroprotection
Astrocyte
Virus infectionVirus infection
QA
Microgilia
neurotoxicity
The upregulation of pro-inflammatory cytokines leads to mood changes and depression through the upregulation of IDO via tryptophan metabolism
We will start by looking at the relationship between INFα and depression
Focus on IDO activity and expression as well as QA and KA activity
Focus on correlation between IDO, TRP, KYN and neurotoxic effects on depression
Lastly, we will look at the correlation between 5-HT, TRP, and depression
Lotrich et al 2007
BDI: Beck depression inventory
INF-α increases depression symptoms in subjects developing major depression ( )Control was not exposed to INF-α:
Sanni et al 1998Sanni et al 1998
Brain IDO activity PbA: Plasmodium berghei ANKA (infected red blood cells) IFN-γ GKO: IFN-γ gene knockout
** p<.0001
Dramatic Changes in Oxidative Tryptophan Dramatic Changes in Oxidative Tryptophan Metabolism along the Kynurenine Pathway in Metabolism along the Kynurenine Pathway in
Experimental Cerebral and Noncerebral Experimental Cerebral and Noncerebral MalariaMalaria
Sanni et al 1998
HPLC analysis of HPLC analysis of IDO activity during IDO activity during EAEEAEKyn/trp ratios taken after immunizing mice
Expression of IDO in the spinal chord of miceExpression of IDO in the spinal chord of miceSection were taken from an animals in the acute phase of EAE (A-D) and from a nonimmunized control animal (E-H)
MARDS: Montagometry Asberg Depression Rating Scale(how the presence of depressive symptoms were assessed)
Capuron et al 2003Capuron et al 2003
Antidepressant-free patients developed major depression during IFN-α therapy remained free of depression during IFN-α therapy
A. TRP concentrationB. KYN concentrationC. KYN/TRP concentration
Savelieva et al 2008Savelieva et al 2008
Marble Burying testDetects compounds having an antidepressant effect
TPH: tryptophan hydroxylase* p<.05 ** p<.0001
Supports
Supports
Supports
Supports
Supports
Supports
The previous findings support my hypothesis:The upregulation of pro-inflammatory cytokines
leads to mood changes and depression through the upregulation of IDO via tryptophan metabolism
Increased levels of proinflammatory cytokines lead to decreased levels of TRP, which affects mood in two different ways:By decreasing serotoninBy increasing production of QA
Future Direction/Experiments
Measure the serotonin effects in Humans at the development of major depressionChecking IDO activity leading to TRP
degradation and measuring the amount of serotonin with/without the overstimulation of IDO
Lotrich FE, Rabinovitz M, Gironda P, Pollock BG. Depression following pegylated interferon-alpha: characteristics and vulnerability. J Psychosom Res. 2007 Aug;63(2):131-5.
Sanni LA, Thomas SR, Tattam BN, Moore DE, Chaudhri G, Stocker R, Hunt NH. Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. Am J Pathol. 1998 Feb;152(2):611-9.
Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpé S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005 Jun;10(6):538-44.
Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry. 2003 Nov 1;54(9):906-14.
Myint AM, Schwarz MJ, Steinbusch HW, Leonard. BENeuropsychiatric disorders related to interferon and interleukins treatment. Metab Brain Dis. 2009 Mar;24(1):55-68. Epub 2008 Dec 10.
Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, Lanthorn TH. Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE. 2008;3(10):e3301. Epub 2008 Oct 15.
Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord. 2005 Oct;88(2):167-73.
Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, Nitsch R, Bechmann I. Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J. 2005 Aug;19(10):1347-9. Epub 2005 Jun 6.
Xu H, Oriss TB, Fei M, Henry AC, Melgert BN, Chen L, Mellor AL, Munn DH, Irvin CG, Ray P, Ray A. Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation. Proc Natl Acad Sci U S A. 2008 May 6;105(18):6690-5. Epub 2008 Apr 24.
Pascal Feunou, Sophie Vanwetswinkel, Florence Gaudray, Michel Goldman, Patrick Matthys, and Michel Y. Braun2. Foxp3CD25 T Regulatory Cells Stimulate IFN—Independent CD152-Mediated Activation of Tryptophan Catabolism That Provides Dendritic Cells with Immune Regulatory Activity in Mice Unresponsive to Staphylococcal Enterotoxin B1. J Immunother. 2008 Nov-Dec;31(9):806-11.