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

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

doi:10.14336/ad.2022.0916

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

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 +5 more·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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Inflammation induces the activation of indoleamine 2,3-dioxygenase (IDO) and diverts tryptophan metabolism from serotonin to kynurenine, reducing the availability of CNS-localized serotonin.
“Moreover, inflammation induces the activation of indoleamine 2,3-dioxygenase (IDO) and diverts TRP metabolism from serotonin to KYN, reducing the availability of CNS-localized serotonin [23].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [23]
Inflammatory conditions stimulate tryptophan degradation and are related to increased levels of kynurenine pathway metabolites in the brain, including neuroprotective KYNA and neurotoxic QUIN.
“This aligns with the notion that inflammatory conditions, despite their generation, stimulate TRP degradation and are related to increased levels of KP metabolites in the brain [23], including the neuroprotective KYNA and neurotoxic QUIN [44].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [23]

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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× · see citing works
“Related underlying mechanisms include NMDAR activation, ROS production [139], lipid peroxidation, and increased levels of nitric oxide synthase [136].”
Background
Serotonin – kynurenine hypothesis of depression: historical overview and recent developments
Oxenkrug, G. (2013) · Current Drug Targets · doi:10.2174/1389450111314050002 · Cited by 156 · see citing works
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 154 · cited 1× · see citing works
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
Background
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 153 · cited 2× · see citing works
“Related underlying mechanisms include NMDAR activation, ROS production [139], lipid peroxidation, and increased levels of nitric oxide synthase [136].”
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 152 · see citing works
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× · see citing works
“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
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 147 · cited 1× · see citing works
“Tetrabenazine is the only approved drug for treating chorea caused by HD [159].”
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× · see citing works
“3-HAA ↑ [70] N [179] N [15] ↑ [93] ↓ [161] ↑ [44]”
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 145 · cited 1× · see citing works
“Alpha-synuclein and dopamine metabolites in the CSF are considered biomarkers of PD [135].”
Background
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× · see citing works
“The levels of L-KYN, 3-HK, and KYNA are elevated in the mouse model of chronic social defeat [82].”
BackgroundInfluential
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 135 · see citing works
Self-citation
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× · see citing works
“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
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 129 · cited 2× · see citing works
“In addition, CA can serve as an AhR ligand to stimulate T cells to produce IL-22[50].”
BackgroundSelf-citation
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 125 · see citing works
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× · see citing works
“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 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 123 · cited 1× · see citing works
“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 120 · cited 1× · see citing works
“showed that IDO2 plays a proinflammatory role in mediating B and Tcell activation in immune responses [20].”
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× · see citing works
“3-HAA ↑ [70] N [179] N [15] ↑ [93] ↓ [161] ↑ [44]”
BackgroundInfluential
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 112 · cited 2× · see citing works
“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
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 107 · cited 1× · see citing works
“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 106 · cited 1× · see citing works
“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
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× · see citing works
“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× · see citing works
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
BackgroundInfluential
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× · see citing works
“This effect is more prominent in women than in men [14].”
Background
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 94 · see citing works
Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid
Tóth, F., Cseh, E., & Vécsei, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010403 · Cited by 92 · cited 1× · see citing works
“Significantly, nanomolar to micromolar levels of KYNA can facilitate AMPA receptor responses [32].”
Background
Serum kynurenic acid is reduced in affective psychosis
Wurfel, B., Drevets, W., Bliss, S., Mcmillin, J., Suzuki, H., Ford, B., Morris, H., Teague, T., Dantzer, R., & Savitz, J. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.88 · Cited by 92 · cited 4× · see citing works
“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× · see citing works
“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
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× · see citing works
“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
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× · see citing works
“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]”
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 89 · cited 2× · see citing works
“Increased 5HT axon density at the injured site is a good indicator of improved functional recovery [110].”
Background
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× · see citing works
“Potent inhibitor of recombinant human IDO [183].”
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 88 · cited 4× · see citing works
“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
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× · see citing works
“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
Melatonin redox activity. Its potential clinical applications in neurodegenerative disorders.
Miller, E., Morel, A., Saso, L., & Saluk, J. (2015) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026615666141209160556 · Cited by 86 · cited 8× · see citing works
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
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× · see citing works
“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 · see citing works
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 84 · cited 3× · see citing works
“It also activates AhR, thus exerting anti-inflammatory and immunoregulatory effects [116].”
Background
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× · see citing works
“Ro 61-8048 Neurodegenerative or neurologic disorders/Preclinical [196] Competitive inhibitor [197]; Poor penetration of BBB in rats [195].”
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 84 · cited 1× · see citing works
“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
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× · see citing works
“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× · see citing works
“Brain TRP ↓ [125] ↓ [181] ↑ [143] ↓ [182]”
Cinnabarinic acid and xanthurenic acid: Two kynurenine metabolites that interact with metabotropic glutamate receptors
Fazio, F., Lionetto, L., Curto, M., Iacovelli, L., Copeland, C., Neale, S., Bruno, V., Battaglia, G., Salt, T., & Nicoletti, F. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.06.020 · Cited by 83 · cited 1× · see citing works
“Aging and Disease • 6 antipsychotic-like effects by positively activating mGlu2 and mGlu3 receptors [49].”
Background
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 81 · cited 1× · see citing works
“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× · see citing works
“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]”
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× · see citing works
“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 · see citing works
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 78 · cited 1× · see citing works
“Another study showed that after increasing IDO1 activity, 3-HAA in KP increased, resulting in an immunosuppressive effect [114].”
Background
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 78 · cited 1× · see citing works
“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 77 · cited 1× · see citing works
“Patients with BD with altered circadian rhythms had reduced levels of melatonin during the euphoric, manic, and depressive phases [78].”
Background
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 77 · cited 2× · see citing works
“KMO converts KYN to 3HK, which is metabolized into the potential neurotoxin QUINA [24].”
Background
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× · see citing works
“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
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 74 · see citing works
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 71 · cited 1× · see citing works
“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]”
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 70 · cited 1× · see citing works
“Dendritic cells also express IDO1 under physiological conditions but are highly induced by traumatic, autoimmune, and neuroinflammatory diseases [15-17].”
Background
Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms.
Aeinehband, S., Brenner, P., Ståhl, S., Bhat, M., Fidock, M., Khademi, M., Olsson, T., Engberg, G., Jokinen, J., Erhardt, S., et al. (2016) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2015.07.016 · Cited by 70 · cited 3× · see citing works
“The accumulation of QUINA is related to the severity of the disease [111].”
BackgroundInfluential
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× · see citing works
“Melatonin ↓ [134] ↓ [134] ↓ [134] ↓ [146]”
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 67 · see citing works
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., Lim, C. K., Jacobs, K. R., Ashton, N., Hye, A., Pedrini, S., Sohrabi, H., Shah, T., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1567-4 · Cited by 66 · cited 4× · see citing works
“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
Crosstalk between Tryptophan Metabolism and Cardiovascular Disease, Mechanisms, and Therapeutic Implications
Liu, G., Chen, S., Zhong, J., Teng, K.-L., & Yin, Y.-L. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1602074 · Cited by 66 · cited 1× · see citing works
“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]”
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., & Wang, D. (2021) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.01.018 · Cited by 65 · cited 2× · see citing works
“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
Kynurenine pathway modulation reverses the experimental autoimmune encephalomyelitis mouse disease progression
Sundaram, G., Lim, C. K., Brew, B., & Guillemin, G. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01844-y · Cited by 65 · cited 1× · see citing works
“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
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 65 · cited 6× · see citing works
“Therefore, more studies are needed to investigate drug candidates with better and superior curative effects with fewer side effects [44].”
BackgroundInfluential
Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer's disease?
Maitre, M., Klein, C., Patte-Mensah, C., & Mensah-Nyagan, A. (2020) · Progress in neurobiology · doi:10.1016/j.pneurobio.2020.101800 · Cited by 63 · cited 1× · see citing works
“TRP metabolites have tremendous therapeutic potential in AD, KYNA, and 5-HIAA and can reduce the accumulation of Aβ in the brain [155].”
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 63 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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
Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.
Toledo-Sherman, L., Prime, M. E., Mrzljak, L., Beconi, M., Beresford, A., Brookfield, F., Brown, C., Cardaun, I., Courtney, S. M., Dijkman, U., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501350y · Cited by 60 · cited 1× · see citing works
“CHDI-340246 HD/Preclinical No therapeutic efficacy in a mouse model of HD [198].”
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× · see citing works
“KYNA levels are elevated in the CSF [131] but decreased in serum [132].”
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 60 · see citing works
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× · see citing works
“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
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 · see citing works
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 · see citing works
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× · see citing works
“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× · see citing works
“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× · see citing works
“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 52 · cited 3× · see citing works
“Brain TRP ↓ [125] ↓ [181] ↑ [143] ↓ [182]”
Background
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 51 · see citing works
Treatment of intracerebral hemorrhage: Current approaches and future directions.
Zhao, W.-B., Wu, C.-J., Stone, C. R., Ding, Y.-C., & Ji, X.-M. (2020) · Journal of Neurological Sciences · doi:10.1016/j.jns.2020.117020 · Cited by 49
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× · see citing works
“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 48 · cited 1× · see citing works
“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
Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder.
Zhou, Y.-L., Zheng, W., Liu, W., Wang, C.-Y., Zhan, Y., Li, H.-Q., Chen, L., & Ning, Y.-P. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.11.001 · Cited by 47 · cited 3× · see citing works
“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., Schwarcz, R., & Hong, L. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0038-4 · Cited by 46 · cited 1× · see citing works
“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
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 44 · cited 1× · see citing works
“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]”
L-DOPA-induced hyperhomocysteinemia in Parkinson's disease: Elephant in the room.
Paul, R., & Borah, A. (2016) · Biochimica et Biophysica Acta · doi:10.1016/j.bbagen.2016.06.018 · Cited by 44 · cited 2× · see citing works
“Aging and Disease • 12 the treatment of PD [156].”
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× · see citing works
“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
Memory and cerebrovascular deficits recovered following angiotensin IV intervention in a mouse model of Alzheimer's disease.
Royea, J., Martinot, P., & Hamel, E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104644 · Cited by 42 · cited 1× · see citing works
“AD is the most common form of dementia, with continuous cognitive impairment and progressive memory loss [123].”
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× · see citing works
“Furthermore, high levels of QUINA are associated with neuronal damage in AD [126].”
Background
Involvement of quinolinic acid in the neuropathogenesis of amyotrophic lateral sclerosis.
Lee, J.-M., Tan, V., Lovejoy, D., Braidy, N., Rowe, D., Brew, B., & Guillemin, G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.05.011 · Cited by 40 · cited 12× · see citing works
“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
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× · see citing works
“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× · see citing works
“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 38 · cited 1× · see citing works
“Therefore, it plays an important role in antioxidant defense and protection against AD [128].”
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
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× · see citing works
“Targeting TRP metabolism can help to elucidate its pathogenic role in various emotional changes induced by TBI [97].”
BackgroundInfluential
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 36 · cited 2× · see citing works
“However, due to its severe adverse effects, it cannot be used currently as a drug in clinical practice [120].”
Background
Grey and white matter structure associates with the activation of the tryptophan to kynurenine pathway in bipolar disorder.
Poletti, S., Melloni, E., 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 35 · cited 1× · see citing works
“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
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× · see citing works
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
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 35 · see citing works
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 35 · see citing works
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., & Bruno, J. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05495-y · Cited by 33 · see citing works
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× · see citing works
“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
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 33 · cited 2× · see citing works
“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
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 · see citing works
Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer's disease.
Toublet, F.-X., Lalut, J., Hatat, B., Lecoutey, C., Davis, A., Since, M., Corvaisier, S., Freret, T., Santos, J. S.-D. O., Claeysen, S., et al. (2020) · European journal of medicinal chemistry · doi:10.1016/j.ejmech.2020.113059 · Cited by 31 · see citing works
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× · see citing works
“3-HK is a product of L-KYN transformed through KMO, which has strong lipophilicity and can easily pass through the BBB [43].”
BackgroundInfluential
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 29 · cited 12× · see citing works
“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., Hamid, H., & Coudoré, F. (2020) · Current Pharmacology Reports · doi:10.1007/s40495-019-00208-2 · Cited by 28 · cited 2× · see citing works
“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
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 · see citing works
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× · see citing works
“found that the expression of QUINA and KYNA increased at 24 and 72 h after partial frontal lobectomy in rats [28].”
Background
Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases
Zhang, S.-W., Collier, M., Heyes, D., Giorgini, F., & Scrutton, N. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108702 · Cited by 26 · cited 1× · see citing works
“Ro 61-8048 Neurodegenerative or neurologic disorders/Preclinical [196] Competitive inhibitor [197]; Poor penetration of BBB in rats [195].”
Background
Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease.
Veres, G., Molnár, M., Zádori, D., Szentirmai, M., Szalardy, L., Török, R., Fazekas, E., Ilisz, I., Vécsei, L., & Klivényi, P. (2015) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2015.03.002 · Cited by 26 · see citing works
The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications
Füvesi, J., Rajda, C., Bencsik, K., Toldi, J., & Vécsei, L. (2012) · Journal of neural transmission · doi:10.1007/s00702-012-0765-3 · Cited by 26 · cited 2× · see citing works
“The third is synthetic drugs with high bioavailability and affinity for excitatory receptor binding sites [119].”
Background
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., 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 25 · cited 2× · see citing works
“However, CA did not confer any therapeutic effects in mice with mGlu4 deficiency [71].”
Background
5-HT1A receptor, 5-HT2A receptor and serotonin transporter binding in the human auditory cortex in depression
Steinberg, L. J., Underwood, M., Bakalian, M. J., Kassir, S., Mann, J., & Arango, V. (2019) · Journal of Psychiatry & Neuroscience · doi:10.1503/jpn.180190 · Cited by 25 · cited 1× · see citing works
“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
Schmidt, S., Siepmann, S., Kuhlmann, K., Meyer, H. E., Metzger, S., Pudelko, S., Leineweber, M., & Däubener, W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044797 · Cited by 25 · cited 1× · see citing works
“(L-1-MT) Depression/Preclinical [187] Poor pharmacokinetics [188]; Competitive inhibitor [189].”
Serotonin Selective Reuptake Inhibitors (SSRIs) and Stroke
Chollet, F., Rigal, J., Marque, P., Barbieux-Guillot, M., Raposo, N., Fabry, V., Albucher, J., Pariente, J., & Loubinoux, I. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0904-9 · Cited by 24 · cited 1× · see citing works
“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
Parasram, K. (2017) · Redox Report · doi:10.1080/13510002.2017.1343223 · Cited by 24 · cited 1× · see citing works
“As a phytochemical with antioxidant and anti-inflammatory activities, phenolic compounds can treat neurodegenerative diseases [151].”
Background
Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders
Nematollahi, A., Sun, G., Jayawickrama, G. S., Hanrahan, J., & Church, W. (2016) · Molecules · doi:10.3390/molecules21070856 · Cited by 23 · cited 2× · see citing works
“disorders/Preclinical [191] KATII selective.”
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× · see citing works
“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].”
Background
Kynurenines and Neurofilament Light Chain in Multiple Sclerosis
Pukoli, D., Polyák, H., Rajda, C., & Vécsei, L. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.658202 · Cited by 22 · cited 1× · see citing works
“↑: 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
Increased plasma melatonin in presymptomatic Huntington disease sheep (Ovis aries): Compensatory neuroprotection in a neurodegenerative disease?
Morton, A. J., Middleton, B., Rudiger, S., Bawden, C., Kuchel, T., & Skene, D. J. (2019) · Journal of Pineal Research · doi:10.1111/jpi.12624 · Cited by 22 · see citing works
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., Szentirmai, M., Bohár, Z., Laborc, K., et al. (2016) · Journal of neural transmission · doi:10.1007/s00702-016-1615-5 · Cited by 21 · cited 1×
“For example, N-(2-N,Ndimethylaminoethyl)-4-oxo-1H-quinoline-2carboxamide hydrochloride, a KYNA analog, has shown therapeutic efficacy [109].”
Background
Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease
Sharma, R., Razdan, K., Bansal, Y., & Kuhad, A. (2018) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2018.1524877 · Cited by 19 · cited 2× · see citing works
“Furthermore, KYNA can function as a noncompetitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAchR) [33].”
Background
Biochemistry and structural studies of kynurenine 3‐monooxygenase reveal allosteric inhibition by Ro 61‐8048
Gao, J., Yao, L.-C., Xia, T., Liao, X., Zhu, D., & Xiang, Y. (2017) · The FASEB Journal · doi:10.1096/fj.201700397rr · Cited by 19 · see citing works
Clinical, genetic, and brain imaging predictors of risk for bipolar disorder in high-risk individuals
Steardo, L., Manchia, M., Carpiniello, B., Pisanu, C., Steardo, L., & Squassina, A. (2020) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2020.1727743 · Cited by 18 · see citing works
The pros and cons of motor, memory, and emotion-related behavioral tests in the mouse traumatic brain injury model
Zhang, R., Wang, J.-M., Huang, L., Wang, T. J., Huang, Y.-R., Li, Z., He, J., Sun, C., Wang, J., Chen, X.-M., et al. (2021) · Neurological Research · doi:10.1080/01616412.2021.1956290 · Cited by 17 · see citing works
Self-citation
Exposure to Elevated Embryonic Kynurenine in Rats: Sex-dependent Learning and Memory Impairments in Adult Offspring
Buck, S. A., Baratta, A., & Pocivavsek, A. (2020) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2020.107282 · Cited by 17 · see citing works
Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease
Boros, F., Klivényi, P., Toldi, J., & Vécsei, L. (2018) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2019.1549231 · Cited by 17 · cited 2× · see citing works
“IDO1 could be a new therapeutic target for HD by regulating inflammatory processes and neurodegeneration and inducing depressive symptoms in HD [145].”
Background
Decreased Expression of Transient Receptor Potential Channels in Cerebral Vascular Tissue from Patients After Hypertensive Intracerebral Hemorrhage
Thilo, F., Suess, O., Liu, Y., & Tepel, M. (2011) · Clinical and experimental hypertension · doi:10.3109/10641963.2011.561903 · Cited by 17 · cited 1×
“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.
Lu, H., Kopcho, L., Ghosh, K., Witmer, M. R., Parker, M. F., Gupta, S., Paul, M., Krishnamurthy, P., Laksmaiah, B., Xie, D., et al. (2016) · Analytical Biochemistry · doi:10.1016/j.ab.2016.02.003 · Cited by 16 · cited 1×
“the rat brain [192]; Low activity against human KATII [19].”
Background
Oral laquinimod treatment in multiple sclerosis.
Fernández, Ó. (2011) · Neurología · doi:10.1016/j.nrl.2010.07.027 · Cited by 16 · cited 1×
“The KYNA analog laquinimod has been used as a diseasemodifying therapy to treat MS in multiple stages [118].”
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×
“84 Experimental/laborator y phase Potent inhibitor [193].”
Ischemic Stroke and Kynurenines: Medicinal Chemistry Aspects.
Hertelendy, P., Toldi, J., Fülöp, F., & Vécsei, L. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867325666180313113411 · Cited by 15 · cited 8×
“Aging and Disease • 2 psychiatric disorders, such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) [2], and in disorders of the central nervous system (CNS), such as spinal cord injury (SCI) [3], traumatic brain injury (TBI), ischemic stroke, and intracerebral hemorrhage (ICH) [4].”
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 · see citing works
Picolinic Acid in Patients with Chronic Hepatitis C Infection: A Preliminary Report
Zuwała−Jagiełło, J., Pazgan−Simon, M., Simon, K. A., & Warwas, M. (2012) · Mediators of Inflammation · doi:10.1155/2012/762863 · Cited by 13 · cited 1× · see citing works
“As a secondary signal for macrophages, PA causes the activation of IFN-γ-primed macrophages and triggers a cytokine-driven inflammatory response [52].”
Background
PEG-Poly(1-Methyl-l-Tryptophan)-Based Polymeric Micelles as Enzymatically Activated Inhibitors of Indoleamine 2,3-Dioxygenase
Huang, G., Tao, A.-Q., Miyazaki, T., Khan, T., Hong, T., Nakagawa, Y., & Cabral, H. (2019) · Nanomaterials · doi:10.3390/nano9050719 · Cited by 12 · cited 1× · see citing works
“(L-1-MT) Depression/Preclinical [187] Poor pharmacokinetics [188]; Competitive inhibitor [189].”
Background
Gender-specific elevation of plasma anthranilic acid in schizophrenia: Protection against glutamatergic hypofunction?
Steiner, J., Dobrowolny, H., Guest, P., Bernstein, H., Fuchs, D., Roeser, J., Summergrad, P., & Oxenkrug, G. (2022) · Schizophrenia Research · doi:10.1016/j.schres.2022.01.048 · Cited by 6 · 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
Antinociceptive effects of the antidepressant phenelzine are mediated by context-dependent inhibition of neuronal responses in the dorsal horn.
Potter, L. E., Doolen, S., Mifflin, K. A., Tenório, G., Baker, G., Taylor, B., & Kerr, B. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.04.047 · Cited by 6 · cited 3× · see citing works
“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].”
Background

Flagged first, then by citations

5 of the 198 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

[72]Oxenkrug G, van der Hart M, Roeser J, Summergrad P (2016). Anthranilic Acid: A Potential Biomarker and Treatment Target for Schizophrenia. Ann Psychiatry Ment Health, 4. PMC4817843 27042691
[79]Kapczinski F, Frey BN, Zannatto V (2004). [ Physiopathology of bipolar disorders: what have changed in the last 10 years?]. Braz J Psychiatry, 26 Suppl 3: 17- 21. 15597134
[93]Jacobs KR, Lovejoy DB (2018). Inhibiting the kynurenine pathway in spinal cord injury: Multiple therapeutic potentials? Neural Regen Res, 13: 2073- 2076. 30323124 PMC6199950
[184]Török N, Tanaka M, Vécsei L (2020). Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway. Int J Mol Sci, 21: 9338 33302404 PMC7762583
[185]Oxenkrug G, van der Hart M, Roeser J, Summergrad P (2017). Peripheral Tryptophan - Kynurenine Metabolism Associated with Metabolic Syndrome is Different in Parkinson's and Alzheimer's Diseases. Endocrinol Diabetes Metab J, in press. PMC5747375 29292800

Sorted by citations

Prebiotics modulate the microbiota-gut-brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice.
de Paiva, I. H. R., Maciel, L. M., da Silva, R. S., Mendonça, I. P., de Souza, J. D., & Peixoto, C. A. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114153 · Cited by 70 · see citing works
Inflammatory Pathogenesis of Post-stroke Depression
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“Serotonin, a key regulator of mood, sleep and memory, is synthesized from Trp. Pro-inflammatory cytokines can accelerate Trp metabolism through the activation of IDO, reducing 5-HT synthesis and increasing neurotoxic quinolinic acid (QA) production, thus contributing to PSD [120].”
The role of the kynurenine pathway in cardiovascular disease
Yang, Y.-H., Liu, X., Liu, X.-Y., Xie, C.-Y., & Shi, J.-W. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1406856 · Cited by 60 · see citing works
Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease
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“This metabolic characteristic is also observed in patients with depression and bipolar disorder [175].”
Self-citation
Immune‐mediated disruption of the blood–brain barrier after intracerebral hemorrhage: Insights and potential therapeutic targets
Jia, P., Peng, Q., Fan, X., Zhang, Y., Xu, H., Li, J., Sonita, H., Liu, S., Le, A. C. T., Hu, Q., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14853 · Cited by 58 · see citing works
“132 Whether the metabolites of M/M have an impact on the BBB function after ICH is also a new research direction.”
BackgroundSelf-citation
Redefining Roles: A Paradigm Shift in Tryptophan–Kynurenine Metabolism for Innovative Clinical Applications
Tanaka, M., Szabó, Á., & Vécsei, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312767 · Cited by 62 · see citing works
“Historical research has uncovered their ability to generate reactive oxygen species (ROS), implicating them in the progression of neurodegenerative diseases through oxidative damage rather than excitotoxicity [80–82] (Table 1).”
Influential
Neuronutrition and Nrf2 Brain Resilience Signaling: Epigenomics and Metabolomics for Personalized Medicine in Nervous System Disorders from Bench to Clinic
Scuto, M. C., Anfuso, C. D., Lombardo, C., Fatta, E. D., Ferri, R., Musso, N., Zerbo, G., Terrana, M., Majzúnová, M., Lupo, G., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199391 · Cited by 28 · see citing works
“Tryptophan (Trp) is an essential aromatic aminoacidic, which can be converted into functional molecules such as serotonin and kynurenine (KYN), both important in regulating the neuronal activity of the nervous system [140].”
Association of the Serotonin and Kynurenine Pathways as Possible Therapeutic Targets to Modulate Pain in Patients with Fibromyalgia
Alfaro-Rodríguez, A., Reyes-Long, S., Roldán-Valadéz, E., González‐Torres, M., Bonilla‐Jaime, H., Bandala, C., Ávila-Luna, A., Bueno-Nava, A., Cabrera-Ruiz, E., Sánchez-Aparicio, P., et al. (2024) · Pharmaceuticals · doi:10.3390/ph17091205 · Cited by 27 · see citing works
“This process subsequently involves several steps leading to the formation of kynurenine, a process pivotal for numerous biological functions, including immune response regulation, neurotransmission, and cellular equilibrium [21].”
BackgroundInfluential
Application and Development of Cell Membrane Functionalized Biomimetic Nanoparticles in the Treatment of Acute Ischemic Stroke
Li, Y., Wu, C., Yang, R., Tang, J., Li, Z.-Q., Yi, X., & Fan, Z.-X. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158539 · Cited by 26
“Meanwhile, L-tryptophan (TRP) plays an important role in the regulation of homeostasis, immunity, and neuronal function [51].”
Background
Targeting 5-HT Is a Potential Therapeutic Strategy for Neurodegenerative Diseases
Xing, C.-C., Chen, H., Bi, W.-Y., Lei, T., Hang, Z.-C., & Du, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413446 · Cited by 25 · see citing works
Hippocampal sclerosis: A review on current research status and its mechanisms
Zhao, T., Cui, X., Zhang, X., Zhao, M., Rastegar‐Kashkooli, Y., Wang, J., Li, Q., Jiang, C. Q., Li, N., Xing, F., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102716 · Cited by 25 · see citing works
Self-citation
Tryptophan metabolism and ischemic stroke: An intricate balance
Yao, C.-J., Xie, D., Zhang, Y.-C., Shen, Y., Sun, P., Ma, Z., Li, J., Tao, J.-M., & Fang, M. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00777 · Cited by 24 · see citing works
Self-citation
Buqi-Huoxue-Tongnao decoction drives gut microbiota-derived indole lactic acid to attenuate ischemic stroke via the gut-brain axis
Liu, Y., Zhao, P., Cai, Z., He, P., Wang, J., He, H., Zhu, Z., Guo, X., Ma, K., Peng, K., et al. (2024) · Chinese Medicine · doi:10.1186/s13020-024-00991-1 · Cited by 24 · see citing works
“Tryp-tophan metabolism is involved in regulating mood and promoting brain development, which is closely associated with central nervous system disorders [54].”
BackgroundSelf-citation
The role of the tryptophan metabolites in gut microbiota-brain axis and potential treatments: a focus on ischemic stroke
Qin, N., Xie, X., Deng, R., Gao, S., & Zhu, T. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1578018 · Cited by 21 · see citing works
Exercise-induced adaptations in the kynurenine pathway: implications for health and disease management
Rangel, M. V. D. S., Lopes, K. G., Qin, X., & Borges, J. P. (2025) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2025.1535152 · Cited by 21 · see citing works
Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage
Zhu, L., Shang, J., Li, Y.-N., Zhang, Z.-Y., Fu, P., Zong, Y., Chen, S., Wang, J.-M., Zhang, J.-W., Wang, J., et al. (2024) · Stroke · doi:10.1161/strokeaha.124.046394 · Cited by 20 · see citing works
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The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain
Martos, D., Lőrinczi, B., Szatmári, I., Vécsei, L., & Tanaka, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063394 · Cited by 25 · see citing works
Postbiotics and the gut–brain axis: A mechanistic review on modulating neuroinflammation and cognitive aging
Lahariya, R., Anand, G., Kumari, B., & Priyadarshi, K. (2026) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2026.578870 · Cited by 17 · see citing works
Tryptophan metabolism at the crossroads of the neuro-immuno-microbial axis: implications for precision medicine in chronic diseases
Xia, H.-H., & Huang, J. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1707850 · Cited by 17 · see citing works
“…as Faecalibacterium prausnitzii ) and I3A-producing lactobacilli , leads to depletion of protective metabolites, resulting in decreased levels of IPA and I3A, insuf ﬁ cient AHR activation, weakened intestinal barrier function, and exacerbated immune imbalance (Huang et al., 2023; Xu et al., 2024).”
Neuroinflammation in Schizophrenia: An Overview of Evidence and Implications for Pathophysiology
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“This process gives rise to a multitude of neuroactive compounds that exert various effects on brain function and dysfunction [157].”
Advancements in the investigation of gut microbiota-based strategies for stroke prevention and treatment
Wang, M., Liu, Y., Zhong, L., Wu, F., & Wang, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1533343 · Cited by 17 · see citing works
“…regulate neurotransmitter activity (26); Trp metabolites are involved in mood and cognitive regulation and possess anti-in ﬂ ammatory properties (27); BAs contribute to neurotransmitter regulation, in ﬂ ammation inhibition, and cognitive enhancement (28); TMAO may increase the risk of stroke,…”
Self-citation
Central post-stroke pain: advances in clinical and preclinical research
Yuan, X., Hu, S., Fan, X.-C., Jiang, C., Xu, Y., Hao, R.-C., Xu, Z., Yu, Y., Rastegar-Kashkooli, Y., Huang, L., et al. (2024) · Stroke and vascular neurology · doi:10.1136/svn-2024-003418 · Cited by 16
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The Connection Between the Oral Microbiota and the Kynurenine Pathway: Insights into Oral and Certain Systemic Disorders
Kis-György, R., Körtési, T., Anicka, A., & Nagy-Grócz, G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46110750 · Cited by 17 · see citing works
Rat models of postintracerebral hemorrhage pneumonia induced by nasal inoculation with Klebsiella pneumoniae or intratracheal inoculation with LPS
Wang, R., Gan, C., Mao, R., Chen, Y., Yan, R., Li, G., Xiong, T., & Guo, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1477902 · Cited by 13 · see citing works
The role of metal ions in stroke: current evidence and future perspectives.
Wang, S.-S., Qin, M., Fan, X.-C., Jiang, C., Hou, Q., Ye, Z., Zhang, X.-R., Yang, Y., Xiao, J., Wallace, K. L., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102498 · Cited by 14 · see citing works
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From Polyphenols to Prodrugs: Bridging the Blood–Brain Barrier with Nanomedicine and Neurotherapeutics
Tanaka, M., Araujo, A. C., Valenti, V. E., Guiguer, E. L., Catharin, V. C. S., Gualhardi, C. M., de Souza Bastos Mazuqueli Pereira, E., de Alvares Goulart, R., de Argolo Haber, R. S., de Carvalho, A. C. A., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052370 · Cited by 13 · see citing works
Peripheral tryptophan-kynurenine pathway dysfunction in first-episode schizophrenia
Li, M., Wu, Y. Z., Xu, Y., Huang, X., Gao, K., Hu, N., Zhu, S., Wang, C., & Liang, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-86390-4 · Cited by 12 · see citing works
“An elevated QUIN/KYNA ratio suggests a shift towards neurotoxic metabolite production, potentially impairing neuroprotective mechanisms and resulting in increased levels of neurotoxic 3-HK and QUIN, while levels of neuroprotective KYNA and XA are reduced 12,32 .”
LC–MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review
Plaatjie, O. N., van Furth, A. M. V., van der Kuip, M., & Mason, S. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1403312 · Cited by 13 · see citing works
Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review
Zhang, J.-B., Zhou, Y.-N., Mei, X., Yan, S., Mao, J., Li, Y., Bian, Z.-H., Li, L., Ji, D., Lu, T.-L., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03763-w · Cited by 12 · see citing works
“PD patients exhibit reduced KYNA levels in the striatum and CSF, coupled with elevated QA concentrations in the striatum and cortex [238].”
Exercise-driven changes in tryptophan metabolism leading to healthy aging
Asante, D. M., Vyavahare, S. S., Shukla, M., McGee‐Lawrence, M. E., Isales, C. M., & Fulzele, S. (2025) · Biochimie · doi:10.1016/j.biochi.2025.11.004 · Cited by 11 · see citing works
Hyperthermia and targeting heat shock proteins: innovative approaches for neurodegenerative disorders and Long COVID
Smadja, D., & Abreu, M. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1475376 · Cited by 12 · see citing works
Galantamine-Memantine Combination in the Treatment of Parkinson’s Disease Dementia
Frost, E. D., Shi, S. X., Byroju, V. V., Rissardo, J. P., Donlon, J., Vigilante, N. F., Murray, B. P., Walker, I. M., McGarry, A. J., Ferraro, T. N., et al. (2024) · Brain Sciences · doi:10.3390/brainsci14121163 · Cited by 20 · see citing works
Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury
Duan, A.-L., Qiu, Y.-J., Song, B.-Y., Tao, Y.-C., Wang, M.-H., Yin, Z.-Q., Xie, M., Chen, Z.-Q., Wang, Z., & Sun, X. (2024) · Biomedicines · doi:10.3390/biomedicines12061178 · Cited by 12 · see citing works
“Kynurenate levels, also known as kynurenic acids (KYNAs) [19], are a downstream product of kynure-nine created through a kynurenic pathway that exhibits a neuroprotective effect in TBI [43].”
Background
Involvement of the tryptophan-kynurenine pathway in the pathogenesis of autoimmune diseases.
Chen, A.-Y., Zhao, Y.-J., Wang, Y.-Y., Wei, W., Hu, W., & Chang, Y. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112837 · Cited by 11 · see citing works
“…by pro-inflammatory factors IFN-γ , it was hypothesized that MS patients would exhibit central nervous system (CNS) inflammation primarily during the acute phase rather than the chronic neurodegenerative phase, with increasing involvement of KP metabolism in MS progression (Huang et al., 2023).”
Shenqi granules enhance recovery from cerebral ischemia-reperfusion injury by modulating tryptophan and tyrosine metabolism and activating NFE2L2/NRF2.
Liu, H.-X., Yang, M.-K., Li, Y.-C., Liu, C.-X., Li, G.-P., Meng, X.-L., Pei, K., & Wen, S.-Y. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156623 · Cited by 11
Vagal innervation limits brain injury by inhibiting gut-selective integrin-mediated intestinal immunocyte migration in intracerebral hemorrhage
Fu, P., Zong, Y., Dai, Y., Zhu, L., Chen, S., Rastegar-Kashkooli, Y., Wang, J.-M., Zhang, J.-W., Wang, J., & Jiang, C. (2024) · Theranostics · doi:10.7150/thno.101680 · Cited by 11
“Therefore, preventing toxic lymphocyte migration from the bloodstream or other immune organs to the brain is a promising way of treating ICH [10, 11].”
BackgroundSelf-citation
The neuroimmune mechanism of pain induced depression in psoriatic arthritis and future directions
Wang, X., Wu, L., Liu, J., Ma, C., Liu, J., & Zhang, Q. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117802 · Cited by 12 · see citing works
Serum neurofilament light chain, inflammatory markers, and kynurenine metabolites in patients with persistent post-concussion symptoms: A cohort study.
Eggertsen, P. P., Palmfeldt, J., Pedersen, A., Frederiksen, O.-V., Olsen, R. J., & Nielsen, J. F. (2024) · Journal of Neurological Sciences · doi:10.1016/j.jns.2024.123016 · Cited by 10 · see citing works
“In a sensitivity analysis, participants with a history of previous psychological and/or psychiatric treatment ( n = 37) were excluded because kynurenine metabolites are known to be associated with psychiatric disorders [16].”
BackgroundInfluential
Gut–Spinal Cord Axis in Spinal Cord Injury: Bidirectional Inflammatory Mechanisms and Microbiota-Targeted Therapeutic Strategies
Dong, J., Xie, T., Shi, C., Feng, G., Zhang, H., Xu, Z., & Dong, L. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s543912 · Cited by 12 · see citing works
“135 TRP is primarily catabolized through the kynurenine pathway (KP), serotonin pathway, and indole pathway, yielding bioactive compounds such as kynurenine (KYN), 5-hydroxytryptamine (5-HT), and various indole derivatives.”
Association between small intestine bacterial overgrowth and psychiatric disorders
Bogielski, B., Michalczyk, K., Głodek, P., Tempka, B., Gębski, W., & Stygar, D. M. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1438066 · Cited by 13 · see citing works
“Moreover, in the striatum of patients with PD, decreased kynurenic acid levels are accompanied by an increase in neurotoxic quinolinic acid (64).”
Background
Harnessing Dietary Tryptophan: Bridging the Gap Between Neurobiology and Psychiatry in Depression Management
Chehadi, A. C., Pereira de Lima, E., Detregiachi, C. R. P., Santos de Argollo Haber, R., Catharin, V. M. C. S., Fornari Laurindo, L., Engracia Valenti, V., Machado Galhardi, C., Tanaka, M., & Maria Barbalho, S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27010465 · Cited by 8 · see citing works
“The problem deepens when pro-inflammatory cytokines activate indoleamine 2,3-dioxygenases (IDOs), shunting Trp down the KYN track, exhausting 5-HT, and generating neurotoxic QA [10,13].”
Influential
The microbiota-gut-brain axis in Huntington’s disease: Evidence, mechanisms and therapeutic opportunities
Gu, Y., Wang, M., & Mao, Y. (2026) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2026.101247 · Cited by 8 · see citing works
Exploring the gut-brain-microbiome axis in Alzheimer's disease: Integrating metagenomics, metabolomics, and artificial intelligence for next-generation biomarker discovery
Oso, T. A., Ahmed, M. M., Okesanya, O. J., Adebayo, U. O., Obadeyi, K. B., Othman, Z. K., & Lucero‐Prisno, D. E. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251407700 · Cited by 7 · see citing works
“74 Notably, indole metabolites, such as 3-indolepropionic acid, are neuroprotective, and their reduction after brain injury is closely linked to extreme neurological results, often in a sex-speci ﬁ c manner.”
Proof of concept study for developing 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors to treat Parkinson's disease complicating depression
Chen, X., Zhu, M., Shi, Q., Huang, Z., Zhu, J., Sun, P., Zhang, H., Yang, L., Chen, X., Zhang, Y., et al. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117597 · Cited by 8 · see citing works
Self-citation
Exploring the role of ubiquitination modifications in migraine headaches
Zhu, Q., Yang, J., Shi, L., Zhang, J.-Y., Zhang, P., Li, J.-L., & Song, X.-L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1534389 · Cited by 8
Indoleamine 2,3-dioxygenase (IDO1) – Can dendritic cells and monocytes expressing this moonlight enzyme change the phase of Parkinson’s Disease?
Gonçalves, M., Rodrigues‐Santos, P., Januário, C., Cosentino, M., & Pereira, F. C. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112062 · Cited by 9 · see citing works
Hepatopancreatic metabolic disorders and their implications in the development of Alzheimer's disease and vascular dementia
Pinheiro, F. I., Araújo-Filho, I., Rêgo, A. C. M., de Azevedo, E. P., Cobucci, R. N., & Gúzen, F. P. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102250 · Cited by 10 · see citing works
Kynurenine pathway dysregulation in major depressive disorder: the convergence of excitotoxicity, neuroinflammation, and oxidative stress
O’Regan, G., Plummer, Z., Christie, B. R., Shultz, S. R., & Allen, J. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03717-2 · Cited by 10 · see citing works
“Both 3-HK and QA promote the production of reactive oxygen species (ROS), increasing oxidative stress, cellular damage, and apoptosis [31–33].”
Beyond Organ Boundaries: Molecular Mechanisms of Hepatic Encephalopathy and Parkinson’s Disease from the Perspective of the Gut–Liver–Brain Axis
Liu, T.-T., Ma, Y., Zhang, M.-D., & Wei, J.-S. (2025) · Research · doi:10.34133/research.1084 · Cited by 7 · see citing works
“In PD, Lewy body deposition in the raphe nucleus causes degeneration of serotonergic neurons, reducing Trp uptake and TPH2 expression to disrupt the same pathway [ 168 ].”
Nutritional effects on mucosal integrity and immune function
Cundra, L. B., Vallabhaneni, M., Houston, K., Saadeh, M., Vargas, A., D’Souza, S. M., & Johnson, D. A. (2024) · Exploration of Immunology · doi:10.37349/ei.2024.00130 · Cited by 9 · see citing works
Environmental Enrichment for Stroke and Traumatic Brain Injury: Mechanisms and Translational Implications
Nie, L., He, J., Wang, J., Wang, R., Huang, L., Jia, L., Kim, Y. T., BHAWAL, U. K., Fan, X., Zille, M., et al. (2023) · Comprehensive physiology · doi:10.1002/j.2040-4603.2024.tb00290.x · Cited by 5 · see citing works
Self-citation
Humanized rodent models of neurodegenerative diseases and other brain disorders
Zhang, X., Wang, J., Zhang, J., Jiang, C., Liu, X., Wang, S., Zhang, Z., Rastegar‐Kashkooli, Y., Dialameh, F., Peng, Q., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106112 · Cited by 6 · see citing works
Self-citation
Sex differences in reward-based operant conditioning performance and neurotransmitter changes following chronic sleep restriction stress in rats
Zhang, Y., Chen, F., Yu, M., Li, Y., Chen, S., Choudhary, M. I., Liu, X., & Jiang, N. (2025) · Behavioral and Brain Functions · doi:10.1186/s12993-025-00268-z · Cited by 5 · see citing works
“These findings are consistent with prior research suggesting that abnormal activation of the TRP-KYN pathway and increased 3-HK levels may contribute to hippocampal dysfunction [28].”
Self-citation
JK5G postbiotics modulate gut microbiota and metabolome to alleviate cancer-related pain: a randomized controlled trial with multi-omics integration
Chen, M., Zhang, J.-H., Yang, H., Lei, L., Yang, L.-J., Wang, S.-X., & Yu, H.-Q. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1764491 · Cited by 5
“This approach advances our understanding of how speci ﬁ c microbial metabolites, including kynurenic acid, may contribute to developing more effective pain management strategies (36, 37).”
Behavioral Balance in Tryptophan Turmoil: Regional Metabolic Rewiring in Kynurenine Aminotransferase II Knockout Mice
Szabó, Á., Galla, Z., Spekker, E., Martos, D., Szűcs, M., Fejes-Szabó, A., Fehér, Á., Takeda, K., Ozaki, K., Inoue, H., et al. (2025) · Cells · doi:10.3390/cells14211711 · Cited by 8 · see citing works
Tryptophan metabolism-related gene CYP1B1 serves as a shared biomarker for both Parkinson’s disease and insomnia
Li, X.-Y., Yu, W.-K., Wu, J.-H., He, W.-J., Cheng, Y.-N., Gao, K., Wei, Y.-H., & Li, Y.-S. (2025) · Scientific Reports · doi:10.1038/s41598-024-84362-8 · Cited by 5 · see citing works
Decreased hippocampal neurogenesis and post-stroke depression
Tang, X., Ran, L., & Li, W. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1761408 · Cited by 5 · see citing works
“This directly leads to reduced central 5-HT availability and the production of potentially neurotoxic catabolites (115 – 117).”
Targeting kynurenine pathway and A1 /A2 astrocytes polarization in experimentally induced fibromyalgia: Modulatory role of apigenin on kynurenine/ aryl hydrocarbon receptor signaling
Al-Matarneh, T. M., El-Said, Y. A. M., Ibrahim, W. W., & El-Tanbouly, D. M. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178408 · Cited by 6 · see citing works
Recent Advances in Ionic Mechanisms in Pituitary Cells: Implications for Electrophysiological and Electropharmacological Research
Wu, S.-N., Wang, Y.-J., Gao, Z.-H., Liutkevičienė, R., & Rovite, V. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14093117 · Cited by 4 · see citing works
“Previous studies have shown that the reduction in the astrocytic formation of KYNA could enhance glutamatergic tone in the hippocampus as well as cognitive abilities and synaptic plasticity [94,98–100].”
Maternal exercise programs placental miR-495-5p-mediated Snx7 expression and kynurenic acid metabolic pathway induced by prenatal high-fat diet: Based on miRNA-seq, transcriptomics, and metabolomics
Li, S., Zhou, L., Ren, J., Zhang, Q., & Xiao, X. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109830 · Cited by 3 · see citing works
Synergism of salvianolic acid B and ginsenoside Rg1 magnifies the therapeutic potency against ischemic stroke
Shen, H., Zhang, Y.-H., Shao, Y., Chen, S., Yin, P., Liu, X., Wang, L.-L., Zhang, L., Jin, Y., Wang, Y., et al. (2024) · NeuroReport · doi:10.1097/wnr.0000000000002099 · Cited by 4
“Tryptophan is metabolized through two main pathways, the kynure-nine pathway and the methoxyindole pathway, both of which are involved in the biosynthesis of proteins that are essential for neuronal construction and maintenance [24,25].”
Self-citation
Ameliorative effect of diclofenac in rotenone corneal kindling model of drug-resistant epilepsy: Edge of dual COX and KMO inhibition.
Samriti, Kaur, A., Kaur, A., & Goel, R. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149246 · Cited by 4 · see citing works
The beneficial effects of modafinil administration on repeat mild traumatic brain injury (RmTBI) pathology in adolescent male rats are not dependent upon the orexinergic system
Christensen, J., Vlassopoulos, E., Barlow, C. K., Schittenhelm, R. B., Li, C. N., Sgro, M., Warren, S., Semple, B. D., Yamakawa, G. R., Shultz, S. R., et al. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114969 · Cited by 4 · see citing works
VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice
Fongsaran, C., Dineley, K. T., Paessler, S., & Cisneros, I. E. (2024) · Pathogens · doi:10.3390/pathogens13050397 · Cited by 3 · see citing works
“Moreover, inﬂammation induces the activation of indoleamine 2,3-dioxygenase (IDO) and diverts TRP metabolism from serotonin to KYN, reducing the availability of CNS-localized serotonin [23].”
Background
Gut-brain axis dysregulation in Parkinson's disease: Mechanisms linking microbiota to neuroinflammation and α-synuclein pathology
Zhao, Z., Dong, M., Mu, Z., ZHENG, Z., & ZHANG, Z. (2025) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2025.101521 · Cited by 4 · see citing works
“These include indole, kynurenine, and indole-3-acetic acid (IAA) [16,118].”
Influx of Metabolites into Cerebrospinal Fluid in Intracerebral Hemorrhage is Associated with Increased Central Inflammation: a Retrospective Observational Study
Zhang, H.-Y., Zhong, Y., Shao, J.-L., Sun, K., Zhang, L., Zhang, Y., Xiao, Y., Zuo, X.-Y., Li, Z.-X., Zeng, T., et al. (2025) · Translational Stroke Research · doi:10.1007/s12975-025-01342-4 · Cited by 3
“The metabolism of L-tryptophan is intricately linked not only to gut microbiota but also to the regulation of homeostasis, immune response, and neuronal function [27, 28].”
Self-citation
Metabolic dysfunction contributes to mood disorders after traumatic brain injury
Liu, L., Jia, P., Liu, T., Liang, J., Dang, Y., Rastegar‐Kashkooli, Y., Li, Q., Liu, J., Man, J., Zhao, T., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102652 · Cited by 3 · see citing works
Self-citation
Norepinephrine-coated defect-engineered chiral MOF enables synergistic enantioseparation in capillary electrochromatography.
Zhai, Z., Guo, C., Liang, L., Du, S.-J., & Du, Y. (2026) · Talanta: The International Journal of Pure and Applied Analytical Chemistry · doi:10.1016/j.talanta.2026.129686 · Cited by 2
Mechanisms of multi-organ damage in Wilson disease from the gut-liver-brain axis perspective: copper metabolism, gut microbiota, and metabolite communication
Wang, X.-Q., Wang, Y.-X., Ye, Z.-H., Zhang, Z.-L., & Cen, S.-F. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1868164 · Cited by 2 · see citing works
The association between depressive symptoms and sleep quality in patients with multiple sclerosis: a systematic review and meta-analysis
Moradi, A., Ebrahimian, A., Talebi, M., & Naseri, A. (2026) · BMC Neurology · doi:10.1186/s12883-026-05075-1 · Cited by 2 · see citing works
“Kynurenine and quinolinic acid are metabolites of this pathway which have immunomodulatory and neurotoxic effects leading to worsening of mood and sleep [97, 98].”
Uncovering parental exposure risks of TCPP: Impaired development and metabolic homeostasis in zebrafish offspring.
Yan, J., Zhao, Z., Li, J.-H., Zhou, X., Fang, L., Ni, A.-Y., Li, J.-Y., Qian, Q.-H., Wang, Z.-J., Wang, H.-L., et al. (2025) · Journal of Environmental Science · doi:10.1016/j.jes.2025.10.031 · Cited by 2
Prenatal Poly I:C exposure affects tryptophan-kynurenine metabolism associated with intestinal microbiome in female juvenile rats
Yang, L.-R., Chen, H.-Y., Zeng, M.-L., Lu, Y.-F., Xu, C., Cao, Z.-J., Zhong, F.-C., Yang, X.-Y., Shen, A.-Y., Su, Y.-Q., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1669845 · Cited by 2 · see citing works
Non-additive effects of microplastics, atrazine, and sulfamethoxazole co-exposure on Penaeus vannamei health and environmental risks.
Wang, Y., Shi, Q., Gan, W., Xu, F., Liu, H., Zhang, L.-Q., Zhang, R.-R., Chen, J., Zhang, Z., & Shi, X.-Z. (2026) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2026.142156 · Cited by 1 · see citing works
Self-citation
Tryptophan Metabolism at the Crossroads of Immunity, Barrier Function, and the Microbiome in Atopic Dermatitis
Tan, Y., Peng, G., Abudouwanli, A., Zhao, W., Sun, Q., Yang, M., Ogawa, H., Okumura, K., & Niyonsaba, F. (2026) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-026-09172-4 · Cited by 1 · see citing works
Buyang Huanwu Decoction promotes neurorepair after spinal cord injury through a Lactobacillus johnsonii–indole-3-lactic acid–AhR–PI3K/Akt axis
Dong, J.-W., Cao, Y., Chen, X.-J., Xie, T., Zhang, X.-B., Zhao, Q.-P., Shi, C., Miao, Q.-X., Xu, Z., Yan, L., et al. (2026) · Chinese Medicine · doi:10.1186/s13020-026-01408-x · Cited by 1 · see citing works
“The gut microbiota can produce metabolites beneficial for SCI repair, among which the tryptophan metabolic pathway is of particular importance [26, 27].”
Self-citation
The Hidden Metabolic Roots of Epilepsy
Rubio, C., Carpinteyro, S., Serrano-García, N., Romo-Parra, H., Pérez-Villavicencio, J., Lee, Á., Mercado-Pimentel, R., & Rubio-Osornio, M. (2026) · Biomedicines · doi:10.3390/biomedicines14040764 · Cited by 1 · see citing works
“Neuroactive metabolites, including quinolinic acid and kynurenic acid, traverse the BBB and influence glutamatergic transmission [129].”
Altered Cerebrospinal Fluid Tryptophan-Kynurenine Pathway Metabolism in Multiple System Atrophy.
Nagao, R., Kawabata, K., Mizutani, Y., Shima, S., Ueda, A., Ito, M., Maeda, Y., Mouri, A., & Watanabe, H. (2026) · Movement Disorders · doi:10.1002/mds.70210 · Cited by 1 · see citing works
Dietary tryptophan intake density and the risk of cardiovascular diseases: insights from a prospective cohort study.
Nguyen, H. L., Le, L. T., Nguyen, T. G., Nguyen, Q. T., van Nguyen, H., & Le, N. T. (2025) · NMCD. Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2025.104468 · Cited by 1 · see citing works
Ido1 or Ido2 deficiency in myeloid-derived cells attenuates TMEV-induced ictogenesis
Kaswan, Z. A. M., Hurtado, M., Chen, E. Y., Steelman, A., & McCusker, R. H. (2025) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2025.578707 · Cited by 1 · see citing works
“These data clearly indicate that deletion of Ido1 or Ido2 in neurons or astrocytes, which have been shown to produce Kyn and then the downstream neuroprotective/anti-ictogenic metabolite kynurenic acid (KynA) [70, 71] , does not exacerbate seizure incidence.”
Myasthenia Gravis and Depression: A Multifaceted Exploration through Omics and Beyond
Guo, Z., Zheng, Y.-L., & Balmer, L. (2025) · ALPHA PSYCHIATRY · doi:10.31083/ap38754 · Cited by 1
“For instance, alterations in tryptophan metabolism, leading to decreased serotonin synthesis, have been observed in both MG and depression [9,10].”
PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer
Yue, X.-Y., Stauff, E., Boyapati, S., Langhans, S. A., Xu, W., Makrogiannis, S., Okorie, U., Okorie, A. M., Kandula, V., Kecskemethy, H., et al. (2024) · Pharmaceuticals · doi:10.3390/ph17060685 · Cited by 1
A Single Exercise Session Elicits a Transient Kynurenine Metabolic Signature in Health and Disease: A Systematic Review and Meta‐Analysis
Rangel, M. V. D. S., Paz, G., Souza, M. D. G. C., Kupjetz, M., Chirino, T. Y. W., Zimmer, P., Farinatti, P., & Borges, J. P. (2026) · The FASEB Journal · doi:10.1096/fj.202603422r
“The balance between these branches is critical for maintaining immune and neuronal homeostasis, positioning the KYN pathway as a promising therapeutic target [12–14].”
Tryptophan metabolism in heart failure: Mechanisms, biomarker potential, and therapeutic implications
Pingge, H. E., Chang, H., Wu, H., Kang, Q., Shaoang, W. A. N. G., Xu, L., & Wang, Z. (2026) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2026.179440
ROS-responsive hydrogel delivering liposomal indole-3-propionic acid promotes spinal cord injury repair by enhancing CX3CL1-CX3CR1 mediated neuron-microglia communication
Li, L.-Y., Zhang, Y.-H., Wang, Z.-S., Li, J.-H., Han, H., Zhang, J.-M., Liu, C., Shang, C.-F., Shang, G.-W., Ji, Y.-H., et al. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.103661
“As one of the three major metabolites of intestinal microorganisms, Tryptophan exhibits significant biological effects in neurological diseases [33].”
Self-citation
Virobiome-mediated regulation of microbiota–gut–brain axis signaling and neuroimmune homeostasis
Afkhamian, A., Natanzi, A. S., Jafaridarabjerdi, M., Aghaei, S., Haghjou, A., Shafiei, M., Bashkandi, A. H., Shahraki, S., Reiter, R. J., Kashani, H. H., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03067-9
“Together, KYNA and QUIN help regulate glutamate homeostasis, neurotransmitter balance, and microglial reactivity, making their modulation by the gut microbiome a promising target for managing neuroinflammatory disorders [219].”
Targeted metabolomics of neurotransmitters and tryptophan reveal neuroprotective effect of Dl-3-n-butylphthalide in cerebral ischemia-reperfusion mice
Wang, Z.-X., Hu, Y., Li, J.-M., Wang, X.-Y., Yuan, B.-Y., Li, J.-M., Luo, Y.-M., & Ma, Q.-F. (2026) · Brain Circulation · doi:10.4103/bc.bc_194_25
Dietary Tryptophan Requirements in Adults Aged Over 60 Years is not Affected by Sex or Decades of Age.
Wang, Z.-Y., Tomlinson, C., Pencharz, P., Li, B.-Q., Kong, D.-H., Elango, R., & Courtney-Martin, G. (2026) · Journal of NutriLife · doi:10.1016/j.tjnut.2026.101827
Targeted quantification of 25 tryptophan metabolites across three metabolic pathways in serum by ultra-high-performance liquid chromatography coupled with quadrupole orbitrap high-resolution mass spectrometry.
Guo, M., Zhang, Z.-H., Cao, L.-P., Wang, S.-H., Xiao, Y., Wang, L.-L., & Zhao, J.-X. (2026) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2026.117729
Bimetallic Ru–Pd Nanoparticles Anchored on Carbon Nanotubes for High-Performance Electrochemical Detection of Tryptophan: Experimental and DFT Insights
Arıcı, Ö. Ö., Najri, B. A., Kavak, E., Çağlar, A., Kıvrak, A., & Kıvrak, H. (2026) · ACS Omega · doi:10.1021/acsomega.6c02081
Gut Microbiota and Ischemic Stroke: From Pre‐Stroke Dysbiosis and Acute‐Phase Changes to Therapeutic Applications
Weng, R., Dong, G., Tang, J., & Zhao, Y. (2026) · Brain and Behavior · doi:10.1002/brb3.71547
Peripheral Kynurenine-to-Tryptophan Ratio as a Candidate Biomarker of Early Neuroinflammatory Dysregulation in First-Episode Drug-Naive Psychosis: A Systematic Review and Meta-Analysis
Thirumalai, J., Mohammed, A. A. F., & Jeslin, G. N. (2026) · SN Comprehensive Clinical Medicine · doi:10.1007/s42399-026-02557-8
Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection
Singh, A. A., Arukha, A. P., & Song, M. (2026) · Molecules · doi:10.3390/molecules31132323
“…kynuramine metabolites, trace quantities of tryptamine, aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), and products of the kynurenine pathway of tryptophan metabolism, such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid, and kynurenic acid [25].”
Microbiota-derived Indole-3-propionic acid improves FFA-induced liver injury in an in vitro model of nonalcoholic fatty liver disease by activating PINK1/parkin-mediated mitophagy.
Liu, Q.-L., Wu, D.-H., Teng, L.-H., Lin, G., Hua, H., & Liang, Z.-H. (2026) · Toxicology in Vitro · doi:10.1016/j.tiv.2026.106279
Relationship between mental disorders and non-traumatic cerebral hemorrhage: cross-sectional analysis and mendelian randomization
Hu, F., Pan, Y., Lu, N.-J., He, J., Zhang, R., Wu, X.-X., Zhang, T., Zhou, H., & Shi, H. (2026) · PeerJ · doi:10.7717/peerj.21385
Self-citation
Insights from LC-MS-based cerebrospinal fluid metabolomics in tuberculous meningitis
Plaatjie, O. N., van Furth, A. M. V., van der Kuip, M., & Mason, S. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1861630
Circadian‐Related Serotonin/Melatonin Level Modulates Cisplatin Ototoxicity Susceptibility Depended on NOS3–NO Pathway
Qiu, S.-Y., Cai, S., Xie, R., Liu, C., & He, Y.-Z. (2026) · Journal of Pineal Research · doi:10.1111/jpi.70154
Kynurenine pathway at the crossroads of neurological and psychiatric disorders: Bridging metabolic dysregulation, therapeutic challenges, and emerging strategies.
Tong, X.-M., Zhan, X., & Zhu, X. (2026) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111796
Effect of transcutaneous electrical acupoint stimulation on postoperative delirium in older patients undergoing laparoscopic gastrointestinal surgery: a randomized controlled trial
Jiang, M.-C., Wang, J., Zhang, J., Zhang, Y., & Li, J. (2026) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2026.102703
Self-citation
Postoperative Serum Quinolinic Acid and 3-Hydroxykynurenine in Dogs with Congenital Portosystemic Shunt: A Pilot Study of Their Association with Postattenuation Neurologic Signs
Mikawa, S., Ishimaru, Y., & Okamura, Y. (2026) · Veterinary Sciences · doi:10.3390/vetsci13040308
“Tryptophan, an essential amino acid, produces various metabolites with important physiological activities and has been associated with neurological and liver diseases [7,8].”
Uncovering the key role of energy metabolism and establishing metabolite-based prognostic biomarkers in ischemic stroke patients undergoing intravenous thrombolysis therapy
Wang, L.-J., Shen, T., Huang, S.-F., Wang, R.-L., Hu, Y., Zhong, L.-Y., Xie, Z.-X., Luo, Y.-M., & Li, S.-J. (2026) · Brain Circulation · doi:10.4103/bc.bc_78_25

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 › 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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