The kynurenine (KYN) pathway, which is initi-ated by indoleamine 2, 3-dioxygenase (IDO), is a key tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Because activation of the KYN pathway by proinflammatory cytokines induces depressive symptoms, shifts in the balance of TRP metabolism to the KYN pathway are closely related to the etiology of depression. In the present study, the influence of age on the effect of the inflammation response system (IRS) on brain TRP metabolism was investigated. Male ICR mice (PND21) were reared for 4 weeks (younger group) or until they reached 1 year of age (older group), and given an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). The TRP, KYN, and 5-HT levels were measured in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei. An increase in TRP and 5-HT levels was observed with age in all brain regions, whereas age was associated with decreases in KYN levels in the dorsal raphe nuclei. In all brain regions, LPS increased TRP levels, while it in-creased KYN levels in the prefrontal cortex and amygdala. Reduced KYN/5-HT ratios in all regions were observed with age, whereas increased KYN/5-HT ratios were observed with LPS in all regions except the dorsal raphe nuclei. Thus, age shifted the balance between the KYN and 5-HT pathways toward the 5-HT pathway, and countered the effects of LPS, which shifted the balance to the KYN pathway. These effects are relevant to the etiology of psychiatric disorders in elderly people.
Maes, M., Scharpe, S., Meltzer, H.Y., Okayli, G., Bosmans, E., D'Hondt, P., Vanden Bossche, B.V. and Cosyns, P. (1994) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Research, 54, 143-160.
Bonaccorso, S., Marino, V., Puzella, A., Pasquini, M., Biondi, M., Artini, M., Almerighi, C., Verkerk, R., Meltzer, H. and Maes, M. (2002) Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. Journal of Clinical Psychopharmacology, 22, 86-90.
Capuron, L., Ravaud, A., Neveu, P.J., Miller, A.H., Maes, M. and Dantzer, R. (2002) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Molecular Psychiatry, 7, 468-473.havior is mediated by indoleamine 2,3-dioxygenase activation in mice. Molecular Psychiatry, 14, 511-522.
Capuron, L., Neurauter, G., Musselman, D.L., Lawson, D.H., Nemeroff, C.B., Fuchs, D., Miller and A.H. (2003) Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biological Psychiatry, 54, 906-914.
Stone, T.W. and Darlington, L.G. (2002) Endogenous kynurenines as targets for drug discovery and development. Nature Reviews Drug Discovery, 1, 609-620.
Konsman, J.P., Parnet, P. and Dantzer, R. (2002) Cytokine-induced sickness behaviour: mechanisms and implications. Trends in Neurosciences, 25, 154-159.
Widner, B., Laich, A., Sperner-Unterweger, B., Ledochowski, M. and Fuchs, D. (2002) Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain, Behavior, and Immunity, 16, 590-595.
Moffett, J.R. and Namboodiri, M.A. (2003) Tryptophan and the immune response. Immunology and Cell Biology, 81, 247- 265.
Myint, A.M. and Kim, Y.K. (2003) Cytokine-serotonin interaction through IDO: A neurodegeneration hypothesis of depression. Medical Hypotheses, 61, 519-525.
Wichers, M.C. and Maes, M. (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. Journal of Psychiatry and Neuroscience, 29, 11-17.
Dantzer, R., Wollman, E., Vitkovic, L. and Yirmiya, R. (1999) Cytokines and depression: Fortuitous or causative association? Molecular Psychiatry, 4, 328-332.
Shimizu, T., Nomiyama, S., Hirata, F. and Hayaishi, O. (1978) Indoleamine 2, 3-dioxygenase. Purification and some properties. Journal of Biological Chemistry, 253, 4700-4706.
Muller, N. and Schwarz, M.J. (2007) The immune-mediated alteration of serotonin and glutamate: Towards an integrated view of depression. Molecular Psychiatry, 12, 988-1000.
Delgado, P.L. (2004) How antidepressants help depression: Mechanisms of action and clinical response. Journal of Clinical Psychopharmacology, 65(4-Supplemnt), 25-30.
Owens, M.J. (2004) Selectivity of antidepressants: From the monoamine hypothesis of depression to the SSRI revolution and beyond. Journal of Clinical Psychophar-macology 65 (4-Supplement), 5-10.
Smith, R.S. (1991) The macrophage theory of depression. Medical Hypotheses, 35, 298-306.
Maes, M., Smith, R. and Scharpe, S. (1995) The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology, 20, 111-116.
Schule, C. (2007) Neuroendocrinological mechanisms of actions of antidepressant drugs. Journal of Neuroendo-crinology, 19, 213-226.
Miura, H., Ozaki, N., Sawada, M., Isobe, K., Ohta, T. and Nagatsu, T. (2008b) A link between stress and depression: Shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress, 11, 198-209.
Kendler, K.S., Kessler, R.C., Neale, M.C., Heath, A.C. and Eaves, L.J. (1993) The prediction of major depression in women: toward an integrated etiologic model. American Journal of Psychiatry, 150, 1139-1148.
Paykel, E.S. (1994) Life events, social support and depression. Acta Psychiatrica Scandinavica, (377 Supplement), 50-58.
Miura, H., Ozaki, N., Shirokawa, T. and Isobe, K. (2008a) Changes in brain tryptophan metabolism elicited by ageing, social environment, and psychological stress in mice. Stress, 11, 160-169.
Miura, H., Qiao, H. and Ohta, T. (2002a) Influence of aging and social isolation on changes in brain monoamine turnover and biosynthesis of rats elicited by novelty stress. Synapse, 46, 116-124.
Miura, H., Qiao, H. and Ohta, T. (2002b) Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress. Brain Research, 926, 10-17.
Miura, H., Qiao, H., Kitagami, T. and Ohta, T. (2004) Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin in the mouse hippocampus. Neuropharmacology, 46, 340-348.
Miura, H., Qiao, H., Kitagami, T., Ohta, T. and Ozaki, N.(2005a) Effects of fluvoxamine on levels of dopamine, serotonin, and their metabolites in the hippocampus elicited by isolation housing and novelty stress in adult rats. International Journal of Neuroscience, 115, 367-378.
Miura, H., Qiao, H., Kitagami, T., Ohta, T. and Ozaki, N. (2005b) Fluvoxamine, a selective serotonin reuptake inhibitor, suppresses tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice. Psychopharmacology (Berl) 177, 307- 314.
Miura, H., Kitagami, T. and Ozaki, N. (2007) Suppressive effect of paroxetine, a selective serotonin uptake inhibitor, on tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice. Synapse, 61, 698-706.
Miura. H., Shirokawa, T., Isobe, K. and Ozaki, N. (2009) Shifting the balance of brain tryptophan metabolism elicited by isolation housing and systemic administration of lipopolysaccharide in mice. Stress, 12, 206-214.
Widner, B., Werner, E.R., Schennach, H., Wachter, H. and Fuchs, D. (1997) Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clinical Chemistry, 43, 2424-2426.
Laich, A., Neurauter, G., Widner, B. and Fuchs, D. (2002) More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC. Clinical Chemistry, 48, 579- 581.
Gramsbergen, J.B., Schmidt, W., Turski, W.A. and Schwarcz, R. (1992) Age-related changes in kynurenic acid production in rat brain. Brain Research, 588, 1-5.
Comai, S., Costa, C.V.L., Ragazzi, E., Bertazzo, A. and Allegri, G. (2005) The effect of age on the enzyme activities of tryptophan metabolism along the kynurenine pathway in rats. Clinica Chimica Acta, 360, 67-80.
Widner, B., Leblhuber, F., Walli, J., Tilz, G.P., Demel, U. and Fuchs, D. (2000) Tryptophan degradation and immune activation in Alzheimer's disease. Journal of Neural Transmission, 107, 343-353.
Frick, B., Schroecksnadel, K., Neurauter, G., Leblhuber, F. and Fuchs, D. (2004) Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clinical Biochemistry, 37, 684-687.
Pertovaara, M., Rhaitala, A., Lehtimaki, T., Karhunen, P.J., Oja, S.S., Jylha, M., Hervonen, A. and Hurme, M. (2006) Indoleamine 2, 3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mechanisms of Ageing and Development, 127, 497-499.
Santiago, M., Machado, A., Reinoso-Suarez, F. and Cano, J. (1988) Changes in biogenic amines in rat hippocampus during development and aging. Life Sciences, 42, 2503-2508.
Delion, S., Chalon, S., Guilloteau, D., Lejeune, B., Besnard, J.C. and Durand, G. (1997) Age-related changes in phospholipid fatty acid composition and monoaminergic neurotransmission in the hippocampus of rats fed a balanced or an n-3 polyunsaturated fatty acid-deficient diet. Journal of Lipid Research, 38, 680-689.
Ponzio, F., Calderini, G., Lomuscio, G., Vantini, G., Toffano, G. and Algeri, S. (1982) Changes in monoamines and their metabolite levels in some brain regions of aged rats. Neurobiology of Aging, 3, 23-29.
Lee, J.M., Ross, E.R., Gower, A., Paris, J.M., Martensson,R. and Lorens, S.A. (1994) Spatial learning deficits in the aged rat: neuroanatomical and neurochemical correlates. Brain Research Bulletin, 33, 489-500.
Gozlan, H., Daval, G., Verge, D., Spampinato, U., Fattaccini, C.M., Gallissot, M.C., el Mestikawy, S. and Hamon, M. (1990) Aging associated changes in serotoninergic and dopaminergic pre- and postsynaptic neurochemical markers in the rat brain. Neurobiology of Aging, 11, 437-449.
Luine, V., Bowling, D. and Hearns, M. (1990) Spatial memory deficits in aged rats: contributions of monoaminergic systems. Brain Research, 537, 271-278.
McMenamy, R.H. (1965) Binding of indole analogues to human serum albumin. Effects of fatty acids. Journal of Biological Chemistry, 240, 4235-4243.
Curzon, G., Friedel, J. and Knott, P.J. (1973) The effect of fatty acids on the binding of tryptophan to plasma protein. Nature, 242, 198-200.
Struder, H.K., Hollmann, W., Platen, P., Wostmann, R., Weicker, H. and Molderings, G.J. (1999) Effect of acute and chronic exercise on plasma amino acids and prolactin concentrations and on [3H]ketanserin binding to serotonin2A receptors on human platelets. European journal of applied physiology and occupational physiology, 79, 318-324.
Fernstrom, J.D. and Wurtman, R.J. (1972) Brain serotonin content: physiological regulation by plasma neutral amino acids. Science, 178, 414-416.
Chaouloff, F. (1997) Effects of acute physical exercise on central serotonergic systems. Medicine & Science in Sports & Exercise, 29, 58-62.
Saito, K., Markey, S.P. and Heyes, M.P. (1992) Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse. Neuroscience, 51, 25-39.
Heyes, M.P., Saito, K., Chen, C.Y., Proescholdt, M.G., Nowak, T.S. Jr., Li, J., Beagles, K.E., Proescholdt, M.A., Zito, M.A., Kawai, K. and Markey, S.P. (1997) Species heterogeneity between gerbils and rats: quinolinate production by microglia and astrocytes and accumulations in response to ischemic brain injury and systemic immune activation. Journal of Neurochemistry, 69, 1519-1529.
Fukui, S., Schwarcz, R., Rapoport, S.I., Takada, Y. and Smith, Q.R. (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. Journal of Neurochemistry, 56, 2007-2017.
Gal, E.M. and Sherman, A.D. (1980) L-kynurenine: its synthesis and possible regulatory function in brain. Petrochemical Research, 5, 223-239.
Kita, T., Morrison, P.F., Heyes, M.P. and Markey, S.P. (2002) Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. Journal of Neurochemistry, 82, 258-268.
Andre, C., O’Connor, J.C., Kelly, K.W., Lestage, J., Danzer, R. and Castanon, N. (2008) Spatio-temporal differences in the profile of murine brain expression expression of proinflammatory cytokines and indoleamine 2, 3-dioxygenase in response to peripheral lipopolysaccharide administration. Journal of Neuroimmunology, 200, 90-99.
O’Connor, J.C., Lawson, M.A., Andre, C., Moreau, M., Lestage, J., Castanon, N., Kelly, K.W. and Dantzer, R. (2009) Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase acti-vation in mice. Molecular Psychiatry, 14, 511-522.
Minami, M., Kuraishi, Y., Yamaguchi, T., Nakai, S., Hirai, Y. and Satoh, M. (1991) Immobilization stress induces interleukin-1 beta mRNA in the rat hypothalamus. Neuroscience Letters, 123, 254-256.
Schulte, H.M., Bamberger, C.M., Elsen, H., Herrmann, G., Bamberger, A.M. and Barth, J. (1994) Systemic inter-leukin-1 alpha and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans. European Journal of Clinical Investigation, 24, 773-777.
Shintani, F., Nakaki, T., Kanba, S., Sato, K., Yagi, G., Shiozawa, M., Aiso, S., Kato, R. and Asai, M. (1995) Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. Journal of Neuroscience, 15, 1961-1970.
Maes, M., Song, C., Lin, A., De Jongh, R., Van Gastel, A., Kenis, G., Bosmans, E., De Meester, I., Benoy, I., Neels, H., Demedts, P., Janca, A., Scharpe, S. and Smith, R.S. (1998) The effects of psychological stress on humans: increased production of proinflammatory cytokines and a Th1-like response in stress-induced anxiety. Cytokine, 10, 313-318.
Nguyen, K.T., Deak, T., Owens, S.M., Kohno, T., Fleshner, M., Watkins, L.R. and Maier, S.F. (1998) Exposure to acute stress induces brain interleukin-1beta protein in the rat. Journal of Neuroscience, 18, 2239-2246.
Burns, A., Gallagley, A. and Byrne, J. (2004) Delirium. Journal of Neurology Neurosurgery and Psychiatry, 75, 362-367.
Inouye, S.K., Studenski, S., Tinetti, M.E. and Kuchel, G.A. (2007) Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. Journal of the American Geriatrics Society, 55, 780-791.
Fong, T.G., Tulebaev, S. R. and Inoue, S.K. (2009) Delirium in elderly adults: diagnosis, prevention and treatment. Nature Reviews Neurology, 5, 210-220.
Maes, M., Meltzer, H.Y., Scharpe, S., Bosmans, E., Suy, E., De Meester, I., Calabrese, J. and Cosyns, P. (1993) Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Research, 49, 151-165.
Maes, M., Wauters, A., Verkerk, R., Demedts, P., Neels, H., Van Gastel, A., Cosyns, P., Scharpe, S. and Desnyder, R. (1996) Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology, 15, 243-251.
Van der Does, A.J. (2001) The effects of tryptophan depletion on mood and psychiatric symptoms. Journal of Affective Disorders, 64, 107-119.