Cited by 138Tryptophan and brain disordersAmino Acid Enzymes and MetabolismTreatment of Major Depression

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Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies

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Huang, Yinrou, Zhao, Mengke, Chen, Xuemei, Zhang, Ruoyu, Le, Anh, Hong, Michael, Zhang, Yufei, Jia, Lin, Zang, Weidong, Jiang, Chao, Wang, Junmin, Fan, Xiaochong, Wang, Jian·2023·Aging and disease

DOI 10.14336/ad.2022.0916PMC PMC10187711

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Abstract

The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3-hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders.

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Figure 1. Tryptophan metabolism by the kynurenine and methoxyindole pathways. Kynurenine is a central KP metabolite capable of degradation through three specific pathways, shown in (1), (2) and (3) in the schematic diagram, to generate different neuroactive metabolites. Abbreviations: TRP, tryptophan; IDO, indoleamine-2,3-dioxygenase; TDO, tryptophan-2,3-dioxygenase; KAT, kynurenine aminotransferase I-III; AA, anthranilic acid; 3-HK, 3-hydroxykynurenine; 3-HAA, 3-hydroxyanthrenillc acid; KMO, kynurenine 3-monooxygenase; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; KP, kynurenine pathway; KYNA, kynurenic acid; PA, picolinic acid; QUINA, quinolinic acid; TPH, tryptophan hydroxylase; CA, cinnabarinic acid; XA, xanthurenic acid; NAD+, nicotinamide adenine dinucleotide; 5-HT, 5-hydroxytryptophan; TPH, tryptophan hydroxylase.CC BY · PubMed Central

Figure 2. The main branches of the kynurenine pathway. TRP, L-KYN, and 3-HK can penetrate the BBB. Thus, they are converted to different intermediates in the extracellular space of brain tissue. TRP is converted to L-KYN by IDO1 in macrophages. L-KYN is converted to KYNA in astrocytes. 3-HK is converted to QUINA by HAAO in microglia. In diseases other than SCZ, KYNA is neuroprotective, as it can remove ROS and inhibit NMDARs, α7nAch, and AMPARs. QUIN is neurotoxic, as it can increase ROS formation, increase glutamate production, and activate NMDARs. Abbreviations: TRP, tryptophan; 3-HK, 3-hydroxykynurenine; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; α7nAChR: α7 nicotinic acetylcholine receptor; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; BBB: blood-brain barrier; IDO, indoleamine-2,3-dioxygenase; KAT, kynurenine aminotransferases I-III; KMO, kynurenine 3-monooxygenase; KYNA, kynurenic acid; L-KYN, L-kynurenine; NMDAR: N-methyl-D-aspartic acid receptor; TRP, tryptophan; QUINA, quinolinic acid; SCZ, schizophrenia; ROS, reactive oxygen speciesCC BY · PubMed Central

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Oxenkrug, G. F. (2013) · Current Drug Targets · doi:10.2174/1389450111314050002 · Cited by 163
Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis
Lovelace, M. D., Varney, B., Sundaram, G., Franco, N. F., Ng, M. L., Pai, S., Lim, C. K., Guillemin, G. J., & Brew, B. J. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00246 · Cited by 161 · cited 1×
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
Background
Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway
Wang, J.-M., Jiang, C., Zhang, K., Lan, X., Chen, X.-M., Zang, W.-D., Wang, Z., Guan, F., Zhu, C.-L., Yang, X., et al. (2019) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2018.12.014 · Cited by 159
Self-citation
Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease
Lim, C. K., Fernández-Gomez, F. J., Braidy, N., Estrada, C., Costa, C., Costa, S., Bessede, A., Fernandez-Villalba, E., Zinger, A., Herrero, M. T., et al. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.009 · Cited by 159 · cited 1×
“Related underlying mechanisms include NMDAR activation, ROS production [139], lipid peroxidation, and increased levels of nitric oxide synthase [136].”
Background
Huntington’s Disease—Update on Treatments
Wyant, K. J., Ridder, A. J., & Dayalu, P. (2017) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-017-0739-9 · Cited by 154 · cited 1×
“Tetrabenazine is the only approved drug for treating chorea caused by HD [159].”
Background
Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway
Török, N., Tanaka, M., & Vécsei, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249338 · Cited by 154
Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease
Chang, K., Cheng, M., Tang, H.-Y., Huang, C.-Y., Wu, Y., & Chen, C. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0845-3 · Cited by 152 · cited 2×
“Related underlying mechanisms include NMDAR activation, ROS production [139], lipid peroxidation, and increased levels of nitric oxide synthase [136].”
Background
The kynurenine pathway in neurodegenerative diseases: mechanistic and therapeutic considerations.
Tan, L., Yu, J.-T., & Tan, L. (2012) · Journal of Neurological Sciences · doi:10.1016/j.jns.2012.08.005 · Cited by 151 · cited 1×
“Therefore, drugs that specifically inhibit KMO activity, such as JM6 and Ro61-8048, can change metabolism to increase KYNA levels and reduce extracellular glutamate in the brain, providing neuroprotection [150].”
Background
Biomarker Research in Parkinson’s Disease Using Metabolite Profiling
Havelund, J. F., Heegaard, N. H. H., Færgeman, N. J., & Gramsbergen, J. B. (2017) · Metabolites · doi:10.3390/metabo7030042 · Cited by 147 · cited 1×
“Alpha-synuclein and dopamine metabolites in the CSF are considered biomarkers of PD [135].”
Background
On the Biological Importance of the 3-hydroxyanthranilic Acid: Anthranilic Acid Ratio
Darlington, L., Forrest, C., Mackay, G. M., Smith, R. A., Smith, A. J., Stoy, N., & Stone, T. W. (2010) · International Journal of Tryptophan Research · doi:10.4137/ijtr.s4282 · Cited by 146 · cited 2×
“3-HAA ↑ [70] N [179] N [15] ↑ [93] ↓ [161] ↑ [44]”
Background
Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36
Li, Q., Lan, X., Han, X., Durham, F., Wan, J., Weiland, A., Koehler, R. C., & Wang, J. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.02.001 · Cited by 136
Self-citation
Identification of Cinnabarinic Acid as a Novel Endogenous Aryl Hydrocarbon Receptor Ligand That Drives IL-22 Production
Lowe, M. M., Mold, J. E., Kanwar, B., Huang, Y., Louie, A., Pollastri, M. P., Wang, C., Patel, G., Franks, D. G., Schlezinger, J. J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087877 · Cited by 136 · cited 2×
“In addition, CA can serve as an AhR ligand to stimulate T cells to produce IL-22[50].”
BackgroundSelf-citation
Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase
Fuertig, R., Azzinnari, D., Bergamini, G., Cathomas, F., Sigrist, H., Seifritz, E., Vavassori, S., Luippold, A., Hengerer, B., Ceci, A., et al. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.12.020 · Cited by 135 · cited 4×
“The levels of L-KYN, 3-HK, and KYNA are elevated in the mouse model of chronic social defeat [82].”
BackgroundInfluential
Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease
Heilman, P. L., Wang, E. W., Lewis, M. M., Krzyżanowski, S., Capan, C. D., Burmeister, A. R., Du, G., Galvis, M. L. E., Brundin, P., Huang, X., et al. (2020) · Movement Disorders · doi:10.1002/mds.28202 · Cited by 134 · cited 1×
“The KYNA level is decreased in the striatum and CSF of patients with PD and correlated with an increase in excitotoxicity, while the QUINA level is increased in the striatum and cortex [138].”
Background
Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease
Bonda, D., Mailankot, M., Stone, J. G., Garrett, M. R., Staniszewska, M. M., Castellani, R. J., Siedlak, S. L., Zhu, X., Lee, H., Perry, G. L., et al. (2010) · Redox Report · doi:10.1179/174329210x12650506623645 · Cited by 126
Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology
Parrott, J. M., & O’Connor, J. C. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00116 · Cited by 125 · cited 1×
“KMO is expressed in resident macrophages in adipose tissue [39] and predominantly in microglia [40] but not in neurons or astrocytes in the brain [41, 42] In TBI or neurodegenerative conditions, the main ratelimiting enzyme in neurotoxicity, KMO, is activated by proinflammatory factors in microglia to generate neuroto…”
Background
Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses
Merlo, L. M. F., DuHadaway, J. B., Montgomery, J. D., Peng, W., Murray, P. J., Prendergast, G. C., Caton, A. J., Muller, A. J., & Mandik‐Nayak, L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01861 · Cited by 124 · cited 1×
“showed that IDO2 plays a proinflammatory role in mediating B and Tcell activation in immune responses [20].”
Background
Expression of functional GPR35 in human iNKT cells.
Fallarini, S., Magliulo, L., Paoletti, T., de Lalla, C., & Lombardi, G. (2010) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2010.06.091 · Cited by 123 · cited 1×
“For example, the KYNAGPR35 interaction can reduce the inflammatory response of mononuclear macrophages to lipopolysaccharide [35] and release cytokines from human invariant natural killer cells [36].”
Background
Kynurenine pathway in Parkinson's disease—An update
Venkatesan, D., Iyer, M., Narayanasamy, A., Siva, K., & Vellingiri, B. (2020) · eNeurologicalSci · doi:10.1016/j.ensci.2020.100270 · Cited by 121 · cited 2×
“However, inhibition of KMOs such as Ro 61-8048 can increase KYNA levels in PD brain tissue [157], which could be a potential drug candidate for”
Background
Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia
Fazio, F., Lionetto, L., Curto, M., Iacovelli, L., Cavallari, M., Zappulla, C., Ulivieri, M., Napoletano, F., Capi, M., Corigliano, V., et al. (2015) · Scientific Reports · doi:10.1038/srep17799 · Cited by 119 · cited 6×
“3-HAA ↑ [70] N [179] N [15] ↑ [93] ↓ [161] ↑ [44]”
BackgroundInfluential
Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines
Zádori, D., Veres, G., Szalárdy, L., Klivènyi, P., & Vécsei, L. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170929 · Cited by 108 · cited 1×
“Deposition of misfolded proteins such as amyloid beta-protein (Aβ) and hyperphosphorylated tau, loss of synaptic transmission, and neuroinflammation are characteristics of AD [124].”
Background
A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder
Sellgren, C. M., Kegel, M. E., Bergen, S. E., Ekman, C. J., Olsson, S., Larsson, M. K., Vawter, M. P., Backlund, L., Sullivan, P. F., Sklar, P. B., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.186 · Cited by 107 · cited 1×
“A postmortem study of the brains of BD patients revealed that downregulation of sorting nexin 7 increased caspase-8-driven interleukin-1β production, subsequently activating the KYN pathway and resulting in neurotoxicity [75].”
Background
Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid
Tóth, F., Cseh, E. K., & Vécsei, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010403 · Cited by 105 · cited 1×
“Significantly, nanomolar to micromolar levels of KYNA can facilitate AMPA receptor responses [32].”
Background
Melatonin Redox Activity. Its Potential Clinical Applications in Neurodegenerative Disorders
Miller, E. D., Morel, A., Saso, L., & Saluk, J. (2014) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666141209160556 · Cited by 105 · cited 8×
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism
Li, Y., Hu, N., Yang, D., Oxenkrug, G. F., & Yang, Q. (2017) · FEBS Journal · doi:10.1111/febs.14026 · Cited by 101 · cited 1×
“TDO is present mainly in the liver [21].”
Background
Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans
Yan, E., Frugier, T., Lim, C. K., Heng, B., Sundaram, G., Tan, M., Rosenfeld, J. V., Walker, D. W., Guillemin, G., & Morganti-Kossmann, M. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0328-2 · Cited by 96 · cited 7×
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
BackgroundInfluential
Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: What do we know and what still needs to be unwrapped?
Pukos, N., Goodus, M. T., Sahinkaya, F. R., & McTigue, D. M. (2019) · Glia · doi:10.1002/glia.23702 · Cited by 95
Anxiety Disorders: Sex Differences in Serotonin and Tryptophan Metabolism.
Songtachalert, T., Roomruangwong, C., Carvalho, A., Bourin, M., & Maes, M. (2018) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026618666181115093136 · Cited by 94 · cited 1×
“This effect is more prominent in women than in men [14].”
Background
Cinnabarinic acid and xanthurenic acid: Two kynurenine metabolites that interact with metabotropic glutamate receptors
Fazio, F., Lionetto, L., Curto, M., Iacovelli, L., Copeland, C. S., Neale, S. A., Bruno, V., Battaglia, G., Salt, T. E., & Nicoletti, F. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.06.020 · Cited by 94 · cited 1×
“Aging and Disease • 6 antipsychotic-like effects by positively activating mGlu2 and mGlu3 receptors [49].”
Background
Serum kynurenic acid is reduced in affective psychosis
Wurfel, B. E., Drevets, W. C., Bliss, S. A., McMillin, J. R., Suzuki, H., Ford, B. N., Morris, H. M., Teague, T. K., Dantzer, R., & Savitz, J. B. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.88 · Cited by 91 · cited 4×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Influential
Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression
Young, K. D., Drevets, W. C., Dantzer, R., Teague, T. K., Bodurka, J., & Savitz, J. B. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.04.007 · Cited by 91 · cited 4×
“A clinical study showed that the ratio of KYNA to 3HK or QUINA is positively associated with hippocampal volume, and decreased hippocampal volume is correlated with impaired autobiographical memory recall in patients with MDD [23].”
BackgroundInfluential
Serotonergic mechanisms in spinal cord injury
Perrin, F. E., & Noristani, H. N. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.05.007 · Cited by 91 · cited 2×
“Increased 5HT axon density at the injured site is a good indicator of improved functional recovery [110].”
Background
Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-α (TNF-α) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils
Tiszlavicz, Z., Németh, B., Fülöp, F., Vécsei, L., Tápai, K., Ocsovszky, I., & Mándi, Y. (2011) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-011-0605-2 · Cited by 89 · cited 1×
“For example, the KYNAGPR35 interaction can reduce the inflammatory response of mononuclear macrophages to lipopolysaccharide [35] and release cytokines from human invariant natural killer cells [36].”
Background
Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations
Bohár, Z., Toldi, J., Fülöp, F., & Vécsei, L. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16059772 · Cited by 89 · cited 4×
“Next we review the role of TRP in multiple sclerosis (MS), an autoimmune disease [5], and neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) [6].”
BackgroundInfluential
Altered tryptophan catabolite concentrations in major depressive disorder and associated changes in hippocampal subfield volumes
Doolin, K., Allers, K. A., Pleiner, S., Liesener, A., Farrell, C., Tozzi, L., O’Hanlon, E., Roddy, D., Frodl, T., Harkin, A., et al. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.05.019 · Cited by 89 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
The IDO Inhibitor Coptisine Ameliorates Cognitive Impairment in a Mouse Model of Alzheimer's Disease
Yu, D., Tao, B.-B., Yang, Y.-Y., Du, L., Yang, S.-S., He, X.-J., Zhu, Y., Yan, J., & Yang, Q. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-140414 · Cited by 88 · cited 1×
“Potent inhibitor of recombinant human IDO [183].”
Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis
Medinas, D., Rozas, P., Traub, F. M., Woehlbier, U., Brown, R. H., Bosco, D. A., & Hetz, C. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1801109115 · Cited by 87 · cited 1×
“ALS is a progressive neurodegenerative disease characterized by selective death of motor neurons in the cerebral cortex, brainstem, and spinal cord, leading to atrophy of voluntary muscles, weakness, paralysis, and premature death [140].”
Background
Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation
Mondanelli, G., Coletti, A., Greco, F. A., Pallotta, M. T., Orabona, C., Iacono, A., Belladonna, M. L., Albini, E., Panfili, E., Fallarino, F., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1918215117 · Cited by 87 · cited 3×
“It also activates AhR, thus exerting anti-inflammatory and immunoregulatory effects [116].”
Background
Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression
Valdés-Tovar, M., Estrada-Reyes, R., Solís-Chagoyán, H., Argueta, J., Dorantes-Barrón, A. M., Quero-Chávez, D., Cruz-Garduño, R., Cercós, M. G., Trueta, C., Oikawa-Sala, J., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14197 · Cited by 85 · cited 1×
“KYNA ↑ [65] ↓ [162] ↓ [163] ↑ [15] ↓ [102] ↑ or ↓* K/T ↑ [65] N [162] ↑ [163] ↑ [15] ↑ [164] ↑ [165] ↑ [44] Melatonin ↓ [166] ↓ [167] ↓ [168] ↓ [18] ↓ [169] ↓ [104] ↓ [170]”
Association of a polymorphism in the indoleamine- 2,3-dioxygenase gene and interferon-α-induced depression in patients with chronic hepatitis C
Smith, A. K., Simon, J. S., Gustafson, E. L., Noviello, S., Cubells, J. F., Epstein, M. P., Devlin, D. J., Qiu, P., Albrecht, J. K., Brass, C. A., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.67 · Cited by 84
The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors
Hughes, T. D., Güner, O. F., Iradukunda, E. C., Phillips, R. S., & Bowen, J. P. (2022) · Molecules · doi:10.3390/molecules27010273 · Cited by 84 · cited 1×
“Ro 61-8048 Neurodegenerative or neurologic disorders/Preclinical [196] Competitive inhibitor [197]; Poor penetration of BBB in rats [195].”
Background
Amino acid metabolism as drug target in autoimmune diseases
Mondanelli, G., Iacono, A., Carvalho, A., Orabona, C., Volpi, C., Pallotta, M. T., Matino, D., Esposito, S., & Grohmann, U. (2019) · Autoimmunity Reviews · doi:10.1016/j.autrev.2019.02.004 · Cited by 84 · cited 1×
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
Background
Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition
Marlatt, M. W., Bauer, J., Aronica, E., van Haastert, E. S., Hoozemans, J. J. M., Joels, M., & Lucassen, P. J. (2014) · Neural Plasticity · doi:10.1155/2014/693851 · Cited by 83 · cited 1×
“Neurotoxic QUINA, mainly produced by activated microglia, can induce tau phosphorylation [129].”
Background
Blood levels of kynurenines, interleukin‐23 and soluble human leucocyte antigen‐G at different stages of Huntington’s disease
Forrest, C., Mackay, G. M., Stoy, N., Spiden, S. L., Taylor, R., Stone, T. W., & Darlington, L. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06442.x · Cited by 83 · cited 2×
“Brain TRP ↓ [125] ↓ [181] ↑ [143] ↓ [182]”
Traumatic Brain Injury: Ultrastructural Features in Neuronal Ferroptosis, Glial Cell Activation and Polarization, and Blood–Brain Barrier Breakdown
Qin, D., Wang, J., Le, A., Wang, T. J., Chen, X., & Wang, J. (2021) · Cells · doi:10.3390/cells10051009 · Cited by 83 · cited 1×
“Inflammation leads to secondary brain damage and promotes ROS formation [94, 95].”
BackgroundSelf-citation
Tryptophan Metabolism, Inflammation, and Oxidative Stress in Patients with Neurovascular Disease
Hajšl, M., Hlaváčková, A., Broulíková, K., Šrámek, M., Malý, M., Dyr, J. E., & Suttnar, J. (2020) · Metabolites · doi:10.3390/metabo10050208 · Cited by 81 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Advances toward precision medicine for bipolar disorder: mechanisms & molecules
Haggarty, S. J., Karmacharya, R., & Perlis, R. H. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0831-4 · Cited by 81 · cited 1×
“However, it has side effects, such as mania, when combined with lithium, and other studies have shown that it has no apparent therapeutic effect [90].”
Background
Melatonin, circadian rhythms, and the clock genes in bipolar disorder
Dallaspezia, S., & Benedetti, F. (2009) · Current Psychiatry Reports · doi:10.1007/s11920-009-0074-1 · Cited by 80 · cited 1×
“Patients with BD with altered circadian rhythms had reduced levels of melatonin during the euphoric, manic, and depressive phases [78].”
Background
Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder
Birner, A., Platzer, M., Bengesser, S., Dalkner, N., Fellendorf, F., Queissner, R., Pilz, R., Rauch, P., Maget, A., Hamm, C., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172699 · Cited by 80 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Targeting kynurenine 3-monooxygenase (KMO): implications for therapy in Huntington's disease.
Thevandavakkam, M., Schwarcz, R., Muchowski, P., & Giorgini, F. (2010) · CNS and Neurological Disorders - Drug Targets · doi:10.2174/187152710793237430 · Cited by 80
The Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes
Meier, T. B., & Savitz, J. B. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.05.021 · Cited by 80 · cited 2×
“KMO converts KYN to 3HK, which is metabolized into the potential neurotoxin QUINA [24].”
Background
Engagement of Nuclear Coactivator 7 by 3-Hydroxyanthranilic Acid Enhances Activation of Aryl Hydrocarbon Receptor in Immunoregulatory Dendritic Cells
Gargaro, M., Vacca, C., Massari, S., Scalisi, G., Manni, G., Mondanelli, G., Mazza, E. M. C., Bicciato, S., Pallotta, M. T., Orabona, C., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01973 · Cited by 79 · cited 1×
“Another study showed that after increasing IDO1 activity, 3-HAA in KP increased, resulting in an immunosuppressive effect [114].”
Background
The tryptophan catabolite or kynurenine pathway in schizophrenia: meta-analysis reveals dissociations between central, serum, and plasma compartments
Almulla, A. F., Vasupanrajit, A., Tunvirachaisakul, C., Al‐Hakeim, H. K., Solmi, M., Verkerk, R. M., & Maes, M. H. J. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01552-4 · Cited by 78 · cited 1×
“showed an increase in IDO activity in brain tissue and peripheral serum and a decrease in KMO activity and a reduction in KYNA production in the brains of SCZ patients [64].”
Background
Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder
Sakurai, M., Yamamoto, Y., Kanayama, N., Hasegawa, M., Mouri, A., Takemura, M., Matsunami, H., Miyauchi, T., Tokura, T., Kimura, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-58806-w · Cited by 76
Dysregulation of kynurenine pathway and potential dynamic changes of kynurenine in schizophrenia: A systematic review and meta-analysis
Cao, B., Chen, Y., Ren, Z., Pan, Z., McIntyre, R. S., & Wang, D. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.01.018 · Cited by 76 · cited 2×
“reported lower levels of TRP and higher KYN/TRP ratios in SCZ patients; lower KYN was associated with SCZ patients without medication, while higher levels of KYN were observed in patients after treatment [63].”
Result
Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis
Iłżecka, J., Kocki, T., Stelmasiak, Z., & Turski, W. (2003) · Acta Neurologica Scandinavica · doi:10.1034/j.1600-0404.2003.00076.x · Cited by 75 · cited 13×
“Activated voluminous microglia, reactive astrocytes, infiltrating macrophages, and T cells are present in the brain and spinal cord of ALS patients, suggesting that these inflammatory cells play a role in the pathogenesis of ALS [144], particularly glutamate excitotoxicity, oxidative stress, mitochondrial metabolic dy…”
BackgroundInfluential
Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms
Aeinehband, S., Brenner, P., Ståhl, S., Bhat, M., Fidock, M. D., Khademi, M., Olsson, T. P., Engberg, G., Jokinen, J., Erhardt, S., et al. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.07.016 · Cited by 74 · cited 3×
“The accumulation of QUINA is related to the severity of the disease [111].”
BackgroundInfluential
Targeting inflammation to influence mood following spinal cord injury: a randomized clinical trial
Allison, D. J., & Ditor, D. S. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0425-2 · Cited by 72 · cited 1×
“KYNA ↑ [65] ↓ [162] ↓ [163] ↑ [15] ↓ [102] ↑ or ↓* K/T ↑ [65] N [162] ↑ [163] ↑ [15] ↑ [164] ↑ [165] ↑ [44] Melatonin ↓ [166] ↓ [167] ↓ [168] ↓ [18] ↓ [169] ↓ [104] ↓ [170]”
Crosstalk between Tryptophan Metabolism and Cardiovascular Disease, Mechanisms, and Therapeutic Implications
Liu, G., Chen, S., Zhong, J., Teng, K., & Yin, Y. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1602074 · Cited by 71 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer’s disease
Chatterjee, P., Zetterberg, H., Goozee, K. G., Lim, C. K., Jacobs, K. R., Ashton, N. J., Hye, A., Pedrini, S., Sohrabi, H. R., Shah, T. M., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1567-4 · Cited by 70 · cited 4×
“One study showed that CSF levels of Aβ40 and Aβ42 correlated with those of K/T, KYNA, L-KYN, QUINA, and AA in AD patients with a high neocortical Aβ load [125].”
BackgroundResultInfluential
Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer’s disease?
Maître, M., Klein, C., Patte‐Mensah, C., & Mensah‐Nyagan, A. G. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101800 · Cited by 69 · cited 1×
“TRP metabolites have tremendous therapeutic potential in AD, KYNA, and 5-HIAA and can reduce the accumulation of Aβ in the brain [155].”
Background
Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer’s Disease
Balmik, A. A., & Chinnathambi, S. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170900 · Cited by 69 · cited 3×
“Melatonin ↓ [134] ↓ [134] ↓ [134] ↓ [146]”
BackgroundInfluential
Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives
Biernacki, T., Sandi, D., Bencsik, K., & Vécsei, L. (2020) · Cells · doi:10.3390/cells9061564 · Cited by 68 · cited 6×
“Therefore, more studies are needed to investigate drug candidates with better and superior curative effects with fewer side effects [44].”
BackgroundInfluential
Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells
Kado, S. Y., Chang, W. L. W., Nguyen, A., Wolny, M., Shepherd, D. M., & Vogel, C. F. A. (2016) · Archives of Toxicology · doi:10.1007/s00204-016-1880-y · Cited by 68
Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease
Toledo, L. M., Prime, M. E., Mrzljak, L., Beconi, M. G., Beresford, A. P., Brookfield, F. A., Brown, C. J., Cardaun, I., Courtney, S. M., Dijkman, U., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501350y · Cited by 67 · cited 1×
“CHDI-340246 HD/Preclinical No therapeutic efficacy in a mouse model of HD [198].”
Background
Modulating 5-Ht 4 and 5-Ht 6 Receptors in Alzheimer’S Disease Treatment
Lalut, J., Karila, D., Dallemagne, P., & Rochais, C. (2017) · Future Medicinal Chemistry · doi:10.4155/fmc-2017-0031 · Cited by 65
Kynurenine pathway modulation reverses the experimental autoimmune encephalomyelitis mouse disease progression
Sundaram, G., Lim, C. K., Brew, B. J., & Guillemin, G. J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01844-y · Cited by 64 · cited 1×
“Preclinical studies have shown that IDO1 activity decreases in the brain and spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), leading to increased Th1 and Th17-cell activity and reduced Treg cell activity, worsening the severity of the disease [112, 113].”
Background
Relevance of Alternative Routes of Kynurenic Acid Production in the Brain
Ramos-Chávez, L. A., Huitrón, R. L., Esquivel, D. G., Pineda, B., Ríos, C., Silva-Adaya, D., Sánchez-Chapul, L., Roldán-Roldán, G., & de la Cruz, V. P. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/5272741 · Cited by 62 · cited 2×
“One recent study demonstrated that KYNA removes ROS as an antioxidant [31].”
Background
Therapeutic role of melatonin in migraine prophylaxis
Long, R.-J., Zhu, Y., & Zhou, S. (2019) · Medicine · doi:10.1097/md.0000000000014099 · Cited by 61 · cited 1×
“KYNA ↑ [65] ↓ [162] ↓ [163] ↑ [15] ↓ [102] ↑ or ↓* K/T ↑ [65] N [162] ↑ [163] ↑ [15] ↑ [164] ↑ [165] ↑ [44] Melatonin ↓ [166] ↓ [167] ↓ [168] ↓ [18] ↓ [169] ↓ [104] ↓ [170]”
The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease
Beaumont, V., Mrzljak, L., Dijkman, U., Freije, R., Heins, M., Rassoulpour, A., Tombaugh, G. C., Gelman, S., Bradaïa, A., Steidl, E., et al. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.05.005 · Cited by 61 · cited 2×
“KYNA is considered protective in BD, but in patients with lifelong psychotic characteristics, elevated KYNA levels in the CSF are correlated with genetic mutations in KMO [77].”
Background
Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study
Chatterjee, P., Goozee, K. G., Lim, C. K., JAMES, I. R., Shen, K., Jacobs, K. R., Sohrabi, H. R., Shah, T. M., Asih, P. R., Dave, P., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-25968-7 · Cited by 60 · cited 1×
“KYNA levels are elevated in the CSF [131] but decreased in serum [132].”
Background
Kynurenine metabolism and inflammation-induced depressed mood: a human experimental study
Kruse, J. L., Cho, J. H.-J., Olmstead, R., Hwang, L., Faull, K., Eisenberger, N. I., & Irwin, M. R. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104371 · Cited by 59 · cited 1×
“In a model of inflammation-induced depression, KYN increased at 2 h, and KYN concentrations decreased back to baseline levels at 6 h [27].”
Background
The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia
Cuartero, M. I., de la Parra, J., García‐Culebras, A., Ballesteros, I., Lizasoaín, I., & Moro, M. Á. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666151214125950 · Cited by 59
Neuroprotective effect of naringenin against MPTP-induced oxidative stress
Sugumar, M., Sevanan, M., & Sekar, S. (2018) · International Journal of Neuroscience · doi:10.1080/00207454.2018.1545772 · Cited by 56
Pharmacological Inhibition of Indoleamine 2,3-Dioxygenase-2 and Kynurenine 3-Monooxygenase, Enzymes of the Kynurenine Pathway, Significantly Diminishes Neuropathic Pain in a Rat Model
Rojewska, E., Ciapała, K., Piotrowska, A., Makuch, W., & Mika, J. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00724 · Cited by 56
Bipolar Disorder: The Role of the Kynurenine and Melatonergic Pathways.
Anderson, G., Jacob, A., Bellivier, F., & Geoffroy, P. (2016) · Current pharmaceutical design · doi:10.2174/1381612822666151214105314 · Cited by 55 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Treatment of intracerebral hemorrhage: Current approaches and future directions
Zhao, W., Wu, C., Stone, C., Ding, Y., & Ji, X. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.117020 · Cited by 55
Physiopathology of ischemic stroke and its modulation using memantine: evidence from preclinical stroke
Martínez‐Coria, H., Arrieta-Cruz, I., Arrieta‐Cruz, I., & López-Valdés, H. E. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.293129 · Cited by 55
Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder
Zhou, Y., Zheng, W., Liu, W., Wang, C., Zhan, Y., Li, H., Chen, L., & Ning, Y. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.11.001 · Cited by 55 · cited 3×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis
Correale, J. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.600428 · Cited by 54 · cited 1×
“Preclinical studies have shown that IDO1 activity decreases in the brain and spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), leading to increased Th1 and Th17-cell activity and reduced Treg cell activity, worsening the severity of the disease [112, 113].”
Background
Increased serum QUIN/KYNA is a reliable biomarker of post-stroke cognitive decline
Cogo, A., Mangin, G., Maïer, B., Callebert, J., Mazighi, M., Chabriat, H., Launay, J., Huberfeld, G., & Kubis, N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00421-4 · Cited by 54 · cited 1×
“Animal experiments show that the QUINA/KYNA ratio increases in mice and gerbils, which is related to immune cell infiltration and the severity of ischemic stroke [101].”
Background
Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis
Tan, V. X., & Guillemin, G. J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01013 · Cited by 54 · cited 3×
“Brain TRP ↓ [125] ↓ [181] ↑ [143] ↓ [182]”
Background
Involvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis
Lee, J., Tan, V. X., Lovejoy, D. B., Braidy, N., Rowe, D. B., Brew, B. J., & Guillemin, G. J. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.05.011 · Cited by 52 · cited 12×
“Activated voluminous microglia, reactive astrocytes, infiltrating macrophages, and T cells are present in the brain and spinal cord of ALS patients, suggesting that these inflammatory cells play a role in the pathogenesis of ALS [144], particularly glutamate excitotoxicity, oxidative stress, mitochondrial metabolic dy…”
BackgroundInfluential
Traumatic Injury Leads to Inflammation and Altered Tryptophan Metabolism in the Juvenile Rabbit Brain
Zhang, Z., Rasmussen, L., Saraswati, M., Koehler, R., Robertson, C., & Kannan, S. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2017.5450 · Cited by 49 · cited 13×
“Targeting TRP metabolism can help to elucidate its pathogenic role in various emotional changes induced by TBI [97].”
BackgroundInfluential
Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid
Fukuwatari, T. (2020) · Nutrients · doi:10.3390/nu12051403 · Cited by 49 · cited 1×
“Furthermore, previous studies have shown that 10 of the 19 amino acids can reduce L-KYN synthesis [91], suggesting that diet therapy can help in the management of mental illness.”
Result
Serotonin and Glutamate Interactions in Preclinical Schizophrenia Models
Shah, U. H., & González‐Maeso, J. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00044 · Cited by 49 · cited 1×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia
Chiappelli, J., Notarangelo, F. M., Pocivavsek, A., Thomas, M. A. R., Rowland, L. M., Schwarcz, R. M., & Hong, L. E. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0038-4 · Cited by 47 · cited 1×
“IDO1 plays a critical pathogenic role in brain disorders when activated by proinflammatory cytokines [12], such as interferon γ (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) [13].”
Background
L-DOPA-induced hyperhomocysteinemia in Parkinson's disease: Elephant in the room
Paul, R. K., & Borah, A. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.06.018 · Cited by 45 · cited 2×
“Aging and Disease • 12 the treatment of PD [156].”
Background
Memory and cerebrovascular deficits recovered following angiotensin IV intervention in a mouse model of Alzheimer's disease
Royea, J., Martinot, P., & Hamel, É. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104644 · Cited by 44 · cited 1×
“AD is the most common form of dementia, with continuous cognitive impairment and progressive memory loss [123].”
Background
Serum indoleamine 2,3-dioxygenase and kynurenine aminotransferase enzyme activity in patients with ischemic stroke
Mo, X.-M., Pi, L., Yang, J., Xiang, Z., & Tang, A. (2013) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2013.08.020 · Cited by 44 · cited 3×
“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Background
Melatonin—A Potent Therapeutic for Stroke and Stroke-Related Dementia
Sadanandan, N., Cozene, B., Cho, J., Park, Y. J., Saft, M., Gonzales-Portillo, B., & Borlongan, C. (2020) · Antioxidants · doi:10.3390/antiox9080672 · Cited by 43 · cited 3×
“Oral melatonin can reduce the severity of stroke patients and improve cognitive decline [104].”
Background
Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis
Rajda, C., Galla, Z., Polyák, H., Maróti, Z., Babarczy, K., Pukoli, D., & Vécsei, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082665 · Cited by 41 · cited 1×
“Furthermore, high levels of QUINA are associated with neuronal damage in AD [126].”
Background
TDO as a therapeutic target in brain diseases
Yu, C., Pan, Z., & Luo, D. (2016) · Metabolic Brain Disease · doi:10.1007/s11011-016-9824-z · Cited by 40 · cited 2×
“Allopurinol Stress/Preclinical Uncertain about structure and lack of clinical trials [190].”
Background
3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture
Ramírez-Ortega, D., Ramiro-Salazar, A., González-Esquivel, D., Ríos, C., Pineda, B., & de la Cruz, V. P. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/2371895 · Cited by 39 · cited 1×
“A recent study demonstrated that 3-HK and 3-HAA increase Cuinduced neurotoxicity in rat astrocyte cultures [133].”
Background
Sex‐specific alterations in NAD+ metabolism in 3xTg Alzheimer’s disease mouse brain assessed by quantitative targeted LC‐MS
van der Velpen, V., Rosenberg, N., Maillard, V., Teav, T., Chatton, J., Gallart‐Ayala, H., & Ivanišević, J. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15362 · Cited by 39 · cited 1×
“Therefore, it plays an important role in antioxidant defense and protection against AD [128].”
Background
Grey and white matter structure associates with the activation of the tryptophan to kynurenine pathway in bipolar disorder
Poletti, S., Melloni, E. M. T., Aggio, V., Colombo, C., Valtorta, F., Benedetti, F., & Comai, S. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.08.034 · Cited by 38 · cited 1×
“Another MRI study showed that the L-KYN/TRP (K/T) ratio in the blood of patients with BD was negatively correlated with amygdala volume, corpus callosum integrity, and frontal-parietal cortex thickness as quantified by MRI [76].”
Background
Activation of alpha7 nicotinic and NMDA receptors is necessary for performance in a working memory task
Phenis, D., Vunck, S. A., Valentini, V., Arias, H., Schwarcz, R. M., & Bruno, J. P. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05495-y · Cited by 38
Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease
Toublet, F., Lalut, J., Hatat, B., Lecoutey, C., Davis, A., Since, M., Corvaisier, S., Fréret, T., Santos, J. S. O., Claeysen, S., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.113059 · Cited by 38
Progress in the development of kynurenine and quinoline-3-carboxamide-derived drugs
Boros, F. A., & Vécsei, L. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1813716 · Cited by 38 · cited 2×
“However, due to its severe adverse effects, it cannot be used currently as a drug in clinical practice [120].”
Background
Melatonin for the treatment of spinal cord injury
Zhang, Y., Zhang, W.-X., Zhang, Y.-J., Liu, Y.-D., Liu, Z.-J., Wu, Q.-C., Guan, Y., & Chen, X. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.238603 · Cited by 37
Self-citation
Pineal gland and schizophrenia: A systematic review and meta-analysis
Bastos, M. A. V., Bastos, P. R. H. D. O., Portella, R. B., Soares, L. F. G., Conde, R. B., Rodrigues, P. M. F., & Lucchetti, G. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.02.024 · Cited by 37
The ‘Yin’ and the ‘Yang’ of the kynurenine pathway: excitotoxicity and neuroprotection imbalance in stress-induced disorders
Barone, P. R. (2019) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000477 · Cited by 37 · cited 2×
“IDO1 plays a critical pathogenic role in brain disorders when activated by proinflammatory cytokines [12], such as interferon γ (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) [13].”
Background
Prospective study of the effects of sport-related concussion on serum kynurenine pathway metabolites
Meier, T. B., Nitta, M. E., Teague, T. K., Nelson, L. D., McCrea, M., & Savitz, J. B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.03.002 · Cited by 37 · cited 12×
“Targeting TRP metabolism can help to elucidate its pathogenic role in various emotional changes induced by TBI [97].”
BackgroundInfluential
Review of Amyotrophic Lateral Sclerosis, Parkinson’s and Alzheimer’s diseases helps further define pathology of the novel paradigm for Alzheimer’s with heavy metals as primary disease cause
Cavaleri, F. (2015) · Medical Hypotheses · doi:10.1016/j.mehy.2015.10.009 · Cited by 36
Exchange-mode glutamine transport across CNS cell membranes
Albrecht, J., & Zielińska, M. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.03.003 · Cited by 35 · cited 8×
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
Xanthurenic Acid Binds to Neuronal G-Protein-Coupled Receptors That Secondarily Activate Cationic Channels in the Cell Line NCB-20
Taleb, O., Maammar, M., Brumaru, D., Bourguignon, J., Schmitt, M., Klein, C., Kemmel, V., Maitre, M., & Mensah-Nyagan, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048553 · Cited by 33 · cited 1×
“It also induces cell apoptosis by altering mitochondrial function and increasing the concentration of intracellular calcium ions, thus playing an excitatory role in the brain [51].”
Background
Multiple Sclerosis and Serotonin: Potential Therapeutic Applications
Hernandez, A. M. S., Singh, C., Valero, D. J., Nisar, J., Ramirez, J. I. T., Suchak, K. K., Isola, S., & Gordon, D. K. (2020) · Cureus · doi:10.7759/cureus.11293 · Cited by 31
The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin
Pawłowski, T., Pawlak, D., Inglot, M., Zalewska, M., Marciniak, D., Bugajska, J., Janocha-Litwin, J., & Małyszczak, K. (2020) · Journal of Psychiatry & Neuroscience · doi:10.1503/jpn.190139 · Cited by 31 · cited 9×
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
The Trace Kynurenine, Cinnabarinic Acid, Displays Potent Antipsychotic-Like Activity in Mice and Its Levels Are Reduced in the Prefrontal Cortex of Individuals Affected by Schizophrenia
Ulivieri, M., Wierońska, J. M., Lionetto, L., Martinello, K., Cieślik, P., Chocyk, A., Curto, M., Menna, L. D., Iacovelli, L., Traficante, A., et al. (2020) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaa074 · Cited by 31 · cited 2×
“However, CA did not confer any therapeutic effects in mice with mGlu4 deficiency [71].”
Background
Plasma Indoleamine-2,3-Dioxygenase (IDO) is Increased in Drug-Naï ve Major Depressed Patients and Treatment with Sertraline and Ketoprofen Normalizes IDO in Association with Pro-Inflammatory and Immune- Regulatory Cytokines
Al‐Hakeim, H. K., Twayej, A. J., Al-Dujaili, A. H., & Maes, M. H. J. (2020) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527319666200102100307 · Cited by 30 · cited 12×
“For MDD patients, two feasible treatment options include the use of KYNA competitive inhibitors, Aging and Disease • 8 such as AV-101, and inhibiting transport of L-KYN to the brain.”
BackgroundInfluential
Neuropathology of Kynurenine Pathway of Tryptophan Metabolism
Tutakhail, A., Boulet, L., Khabil, S., Nazari, Q. A., Hamid, H., & Coudoré, F. (2020) · Current Pharmacology Reports · doi:10.1007/s40495-019-00208-2 · Cited by 28 · cited 2×
“The K/T ratio and 3-HK levels in the putamen, frontal cortex, and hippocampus of PD patients is significantly increased, indicating an increase in IDO/TDO activity in PD patients [137].”
Background
Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial
Cambron, M., Mostert, J., D'Hooghe, M., Nagels, G., Willekens, B., Debruyne, J., Algoed, L., Verhagen, W., Hupperts, R., Heersema, D., et al. (2019) · Multiple Sclerosis · doi:10.1177/1352458519843051 · Cited by 28 · cited 1×
“However, clinical trials have shown that fluoxetine, another drug that can increase the 5-HT concentration in the brain, did not benefit MS patients significantly [122].”
Background
Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease
Veres, G., Molnar, M. F., Zádori, D., Szentirmai, M., Szalárdy, L., Maszlag-Török, R., Fazekas, E., Ilisz, I., Vécsei, L., & Klivènyi, P. (2015) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2015.03.002 · Cited by 28
Urinary kynurenine as a biomarker for Parkinson’s disease
Bai, J.-H., Zheng, Y.-L., & Yu, Y.-P. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04589-x · Cited by 27
Modification of Kynurenine Pathway via Inhibition of Kynurenine Hydroxylase Attenuates Surgical Brain Injury Complications in a Male Rat Model
Zakhary, G., Sherchan, P., Li, Q., Tang, J.-P., & Zhang, J. H. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24489 · Cited by 27 · cited 1×
“found that the expression of QUINA and KYNA increased at 24 and 72 h after partial frontal lobectomy in rats [28].”
Background
A comparative assessment of two kynurenic acid analogs in the formalin model of trigeminal activation: a behavioral, immunohistochemical and pharmacokinetic study
Veres, G., Fejes-Szabó, A., Zádori, D., Nagy-Grócz, G., László, A., Bajtai, A., Mándity, I. M., Szentirmai, M., Bohár, Z., Laborc, K. F., et al. (2016) · Journal of Neural Transmission · doi:10.1007/s00702-016-1615-5 · Cited by 27 · cited 1×
“For example, N-(2-N,Ndimethylaminoethyl)-4-oxo-1H-quinoline-2carboxamide hydrochloride, a KYNA analog, has shown therapeutic efficacy [109].”
Background
Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases
Zhang, S., Collier, M. E. W., Heyes, D. J., Giorgini, F., & Scrutton, N. S. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108702 · Cited by 26 · cited 1×
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Background
The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications
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“Furthermore, previous studies have shown TRP depletion in the brains of MDD patients with decreased availability of the serotonin-1A receptor and the -2A receptor [87].”
Background
Influence of Tryptophan Contained in 1-Methyl-Tryptophan on Antimicrobial and Immunoregulatory Functions of Indoleamine 2,3-Dioxygenase
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“disorders/Preclinical [191] KATII selective.”
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“IDO ↑ [65] ↑ [171] ↑ [172] ↑ [18] ↑ [107] ↑ [102] ↑ [173] 5-HT ↑ [174] ↓ [79] ↑ [88] ↓ [18] ↓ [110] ↓ [175] ↓ [115] L-KYN ↑ [63] N [162] N [163] ↑ [15] ↑ [93] ↑ [176] ↑ [116] 3-HK ↑ [8] ↑ [177] ↑ [82] ↑ [96] ↑ [93] ↑ [178] ↑ [44]”
Phytochemical treatments target kynurenine pathway induced oxidative stress
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Kynurenines and Neurofilament Light Chain in Multiple Sclerosis
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“↑: increase; ↓: decrease; N: nonsignificant difference; - uncertainty # There was no difference in the CSF level of QUINA between MS patients and normal subjects, but QUINA was increased in patients with relapsingremitting MS (RRMS) in the relapse stage [180].”
Background
Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis
Lemos, H. D. P., Mohamed, E. T., Ou, R., McCardle, C., Zheng, X., McGuire, K., Homer, N. Z. M., Mole, D. J., Huang, L., & Mellor, A. L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01256 · Cited by 23 · cited 1×
“Previous studies suggest that increasing IDO activity and inhibiting the production of downstream catabolic products hinder the progression of EAE and may be a new therapeutic strategy [117].”
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Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease
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“Furthermore, KYNA can function as a noncompetitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAchR) [33].”
Background
Exposure to elevated embryonic kynurenine in rats: Sex-dependent learning and memory impairments in adult offspring
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Background
Biochemistry and structural studies of kynurenine 3‐monooxygenase reveal allosteric inhibition by Ro 61‐8048
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PEG-Poly(1-Methyl-l-Tryptophan)-Based Polymeric Micelles as Enzymatically Activated Inhibitors of Indoleamine 2,3-Dioxygenase
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Self-citation
Decreased Expression of Transient Receptor Potential Channels in Cerebral Vascular Tissue from Patients After Hypertensive Intracerebral Hemorrhage
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“However, very few studies have investigated the effects of TRP metabolism in preclinical and clinical ICH studies [106], indicating a new direction of research.”
Background
Development of a RapidFire mass spectrometry assay and a fluorescence assay for the discovery of kynurenine aminotransferase II inhibitors to treat central nervous system disorders.
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Background
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Method
Designing a natural inhibitor against human kynurenine aminotransferase type II and a comparison with PF-04859989: a computational effort against schizophrenia
Noorbakhsh, A., Koushki, E. H., Farshadfar, C., & Ardalan, N. (2021) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2021.1893817 · Cited by 15 · cited 1×
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BackgroundInfluential
Improvement of kynurenine aminotransferase-II inhibitors guided by mimicking sulfate esters
Jayawickrama, G. S., Nematollahi, A., Sun, G., & Church, W. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196404 · Cited by 14
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BackgroundInfluential
Antinociceptive effects of the antidepressant phenelzine are mediated by context-dependent inhibition of neuronal responses in the dorsal horn.
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BackgroundSelf-citation

See all 138

Authors: Huang, Y., Zhao, M., Chen, X., Zhang, R., Le, A., Hong, M., Zhang, Y., Jia, L., Zang, W., Jiang, C., Wang, J., Fan, X., & Wang, J.
Affiliations: First Affiliated Hospital of Zhengzhou University (CN)
Zhengzhou University (CN)
Washington University in St. Louis (US)
Sinai Hospital (US)
University of Washington (US)
Fifth Affiliated Hospital of Zhengzhou University (CN)
Corresponding author: Wang, Junmin
Fan, Xiaochong
Wang, Jian
ORCID: Zhao, Mengke
Chen, Xuemei
Zhang, Ruoyu
Le, Anh
Hong, Michael
Zhang, Yufei
Zang, Weidong
Jiang, Chao
Wang, Junmin
Fan, Xiaochong
Wang, Jian
Venue: Aging and disease
Publisher: Aging and Disease
Published: 2023
Volume: 14
Issue: 3
Pages: 858
ISSN: 2152-5250 (ISSN-L)
DOI: 10.14336/ad.2022.0916
PMC: PMC10187711
OpenAlex: W4312580438
Cited by: 138
References: 198
Citations by year: 2026: 45 · 2025: 55 · 2024: 36 · 2023: 2
FWCI: 1.76
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Aging and Disease (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Zhengzhou University
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: tryptophan metabolism, kynurenine pathway, central nervous system disorders, schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, kynurenic acid, quinolinic acid, serotonin, melatonin, biomarkers, treatment options

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Tryptophan Metabolism in Central Nervous System Diseases: Pathophysiology and Potential Therapeutic Strategies

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