{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:11Z","timestamp":1787028551600,"version":"build-2736575974"},"reference-count":105,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cognitive impairment is a core feature of neurodevelopmental (schizophrenia) and aging-associated (mild cognitive impairment and Alzheimer\u2019s dementia) neurodegenerative diseases. Limited efficacy of current pharmacological treatments warrants further search for new targets for nootropic interventions. The breakdown of myelin, a phospholipids axonal sheath that protects the conduction of nerve impulse between neurons, was proposed as a neuropathological abnormality that precedes and promotes the deposition of amyloid-\u03b2 in neuritic plaques. The present review of the recent literature and our own pre- and clinical data suggest (for the first time) that the anthranilic acid (AA)-induced activation of microglial-expressed G-protein coupled receptor (GPR109A) inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that triggers the degradation of myelin and consequently attenuates cognitive impairment. The present review suggests that the up-regulation of AA formation is a sex-specific compensatory (adaptive) reaction aimed to prevent\/treat cognitive impairment. The AA\u2013GPR109A\u2013cPLA2\u2013myelin\u2013cognition cascade suggests new nootropic interventions, e.g., the administration of pegylated kynureninase, an enzyme that catalyzes AA formation from Kynurenine (Kyn), a tryptophane catabolite; pegylated interferon-alpha; central and peripheral Kyn aminotransferase inhibitors that increase availability of Kyn as a substrate for AA formation; and vagus nerve stimulation. The cascade predicts nootropic activity of exogenous GPR109A agonists that were designed and underwent clinical trials (unsuccessful) as anti-dyslipidemia agents. The proposed cascade might contribute to the pathogenesis of cognitive impairment. Data on AA in neurodegenerative disorders are scarce, and the proposed cascade needs further exploration in pre- and clinical studies<\/jats:p>","DOI":"10.3390\/ijms252413269","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T12:22:06Z","timestamp":1733833326000},"page":"13269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Anthranilic Acid\u2013G-Protein Coupled Receptor109A\u2013Cytosolic Phospholipase A2\u2013Myelin\u2013Cognition Cascade: A New Target for the Treatment\/Prevention of Cognitive Impairment in Schizophrenia, Dementia, and Aging"],"prefix":"10.3390","volume":"25","author":[{"given":"Gregory","family":"Oxenkrug","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jalz.2007.01.019","article-title":"Human brain myelination and amyloid beta deposition in Alzheimer\u2019s disease","volume":"3","author":"Bartzokis","year":"2007","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"698","DOI":"10.14336\/AD.2023.0628","article-title":"Myelin Pathology in Alzheimer\u2019s Disease: Potential Therapeutic Opportunities","volume":"15","author":"Zhang","year":"2024","journal-title":"Aging Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1038\/s41467-020-16218-4","article-title":"Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia","volume":"11","author":"Maas","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/sj.npp.1300180","article-title":"Myelination and Brain Electrophysiology in Healthy and Schizophrenic Individuals","volume":"28","author":"Bartzokis","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kister, A., and Kister, I. (2022). Overview of myelin, major myelin lipids, and myelin-associated proteins. Front. Chem., 10.","DOI":"10.3389\/fchem.2022.1041961"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1038\/s41593-024-01749-6","article-title":"Oligodendroglial fatty acid metabolism as a central nervous system energy reserve","volume":"27","author":"Asadollahi","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.5114\/aoms.2018.76863","article-title":"The role of myelin damage in Alzheimer\u2019s disease pathology","volume":"16","author":"Konrad","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.brainresbull.2017.12.013","article-title":"Myelin changes at the early stage of 5XFAD mice","volume":"137","author":"Gu","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eabl7634","DOI":"10.1126\/scitranslmed.abl7634","article-title":"The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer\u2019s disease","volume":"14","author":"Moutinho","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1001\/jamaneurol.2016.3232","article-title":"Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease","volume":"74","author":"Dean","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1002\/alz.12968","article-title":"Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals","volume":"19","author":"Gong","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/00001756-199802160-00013","article-title":"MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia","volume":"9","author":"Buchsbaum","year":"1998","journal-title":"NeuroReport"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1002\/cne.10714","article-title":"Marked loss of myelinated nerve fibers in the human brain with age","volume":"462","author":"Marner","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40035-022-00321-1","article-title":"Myelin repair in Alzheimer\u2019s disease: A review of biological pathways and potential therapeutics","volume":"11","author":"Hirschfeld","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0920-9964(94)90043-4","article-title":"The membrane hypothesis of schizophrenia","volume":"13","author":"Horrobin","year":"1994","journal-title":"Schizophr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ansarey, S.H. (2021). Inflammation and JNK\u2019s role in Niacin-GPR109A diminished flushed effect in microglial and neuronal cells with relevance to schizophrenia. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.771144"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S1044-7431(03)00241-0","article-title":"Phospholipase A2 plays an important role in myelin breakdown and phagocytosis during wallerian degeneration","volume":"24","author":"De","year":"2003","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/sj.mp.4001325","article-title":"Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: An in vivo 31P MRS study","volume":"8","author":"Keshavan","year":"2003","journal-title":"Mol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1007\/s12035-012-8279-4","article-title":"Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer\u2019s Disease Pathogenesis","volume":"45","author":"Gentile","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/sj.mp.4002000","article-title":"Metabolomic mapping of atypical antipsychotic effects in schizophrenia","volume":"12","author":"McEvoy","year":"2007","journal-title":"Mol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1172\/JCI118117","article-title":"Identification of the mechanism for the inhibition of Na+, K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2","volume":"96","author":"Xia","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0091-3057(79)90216-8","article-title":"Scotophobin A causes dark avoidance in goldfish by elevating pineal N-acetylserotonin","volume":"10","author":"Satake","year":"1979","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1749-6632.2009.05354.x","article-title":"Quinone reductase 2 and antidepressant effect of melatonin derivatives","volume":"1199","author":"Oxenkrug","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1042\/bj3510709","article-title":"Negative regulation of cytosolic phospholipase A2 by melatonin in the rat pineal gland","volume":"351","author":"Beibei","year":"2000","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1749-6632.1999.tb07990.x","article-title":"N-acetyl-serotonin, melatonin and their derivatives improve cognition and protect against b-amyloid-induced neurotoxicity","volume":"890","author":"Bachurin","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","first-page":"330","article-title":"N-acetylserotonin and aging-associated cognitive impairment and depression","volume":"3","author":"Oxenkrug","year":"2012","journal-title":"Aging Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"514","DOI":"10.2174\/1389450111314050002","article-title":"Serotonin-kynurenine hypothesis of depression: Historical overview and recent developments","volume":"14","author":"Oxenkrug","year":"2013","journal-title":"Curr. Drug Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E549","DOI":"10.1152\/ajpendo.91004.2008","article-title":"Niacin stimulates adiponectin secretion through the GPR109A receptor","volume":"296","author":"Plaisance","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7653","DOI":"10.1021\/jm800896z","article-title":"Nicotinic acid receptor agonists","volume":"51","author":"Boatman","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1043-2760(00)00370-2","article-title":"Is There Astrocyte-Neuron Ketone Body Shuttle?","volume":"12","author":"Guzman","year":"2001","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109456","DOI":"10.1016\/j.neuropharm.2023.109456","article-title":"Potential role of the hydroxyl carboxylic acid receptor type 2 (HCAR2) in microglia pathophysiology: A possible cross-talk with C-X-C chemokine receptor 1 (CXCR1)","volume":"228","author":"Perrone","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S2215-0366(17)30101-3","article-title":"Brain microglia in psychiatric disorders","volume":"4","author":"Mondelli","year":"2017","journal-title":"Lancet Psychiat"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhang, G., Wang, Z., Hu, H., Zhao, M., and Sun, L. (2021). Microglia in Alzheimer\u2019s Disease: A Target for Therapeutic Intervention. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.749587"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8044","DOI":"10.18632\/aging.102343","article-title":"GPR109A activation and aging liver","volume":"11","author":"Ravirajsinh","year":"2019","journal-title":"Aging"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.bbrc.2012.07.082","article-title":"Effects of high fat diet on GPR109A and GPR81 gene expression","volume":"425","author":"Wanders","year":"2012","journal-title":"Biochem. Biophys. Res. Comm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5440","DOI":"10.1073\/pnas.97.10.5440","article-title":"D-beta-hydroxybutyrate protects neurons in models of Alzheimer\u2019s and Parkinson\u2019s disease","volume":"97","author":"Kashiwaya","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1007\/s00213-020-05467-2","article-title":"Effects of beta-hydroxybutyrate administration on MK-801-induced schizophrenia-like behaviour in mice","volume":"237","author":"Kraeuter","year":"2020","journal-title":"Psychopharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12974-014-0230-3","article-title":"Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson\u2019s disease models are mediated by GPR109A-dependent mechanisms","volume":"12","author":"Fu","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1136\/jnnp.2003.025858","article-title":"Dietary niacin and the risk of incident Alzheimer\u2019s disease and of cognitive decline","volume":"75","author":"Morris","year":"2004","journal-title":"J. Neurol. Neurosur. Psychiat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"799","DOI":"10.2147\/NDT.S157055","article-title":"Serum levels of \u03b2-hydroxybutyrate and pyruvate, metabolic changes and cognitive function in patients with schizophrenia during antipsychotic treatment: A preliminary study","volume":"14","author":"Huang","year":"2018","journal-title":"Neuropsychiat. Dis. Treat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1158\/0008-5472.CAN-08-4466","article-title":"GPR109A is a G-protein\u2013coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon","volume":"69","author":"Thangaraju","year":"2009","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1038\/s41388-023-02700-y","article-title":"Elevated serum \u03b2-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1","volume":"42","author":"Mao","year":"2023","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3426","DOI":"10.1016\/j.bmcl.2010.04.001","article-title":"Anthranilic acid replacements in a niacin receptor agonist","volume":"20","author":"Schmidt","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12974-019-1552-y","article-title":"Butyrate suppresses demyelination and enhances remyelination","volume":"16","author":"Chen","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shaw, C., Hess, M., and Weimer, B.C. (2023). Microbial-derived tryptophan metabolites and their role in neurological disease: Anthranilic acid and anthranilic acid derivatives. Microorganisms, 11.","DOI":"10.3390\/microorganisms11071825"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrn3257","article-title":"Kynurenines in the mammalian brain: When physiology meets pathology","volume":"13","author":"Schwarcz","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.neuropharm.2016.08.003","article-title":"The kynurenine pathway and the brain: Challenges, controversies and promises","volume":"112","author":"Schwarcz","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.abb.2013.10.020","article-title":"Structure and mechanism of kynureninase","volume":"544","author":"Phillips","year":"2014","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0014-2999(99)00196-X","article-title":"Tryptophan metabolism and brain function: Focus on kynurenine and other indole metabolites","volume":"375","author":"Moroni","year":"1999","journal-title":"Eur. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1093\/schbul\/sbq112","article-title":"Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia","volume":"37","author":"Sathyasaikumar","year":"2011","journal-title":"Schizophr. Bull."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0006-3223(01)01078-2","article-title":"Increased cortical kynurenate content in schizophrenia","volume":"50","author":"Schwarcz","year":"2001","journal-title":"Biol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.physbeh.2007.05.025","article-title":"The kynurenic acid hypothesis of schizophrenia","volume":"92","author":"Erhardt","year":"2007","journal-title":"Physiol. Behav."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bbr.2016.09.050","article-title":"Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions","volume":"317","author":"Tashiro","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jchromb.2012.04.030","article-title":"Development and validation of a single analytical method for the determination of tryptophan, and its kynurenine metabolites in rat plasma","volume":"898","author":"Harvey","year":"2012","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1111\/j.1471-4159.1991.tb03460.x","article-title":"Blood-brain barrier transport of kynurenines: Implications for brain synthesis and metabolism","volume":"56","author":"Fukui","year":"1991","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2022\/5019752","article-title":"Kynurenine pathway metabolites in the blood and cerebrospinal fluid are associated with human aging","volume":"2022","author":"Solvang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neurobiolaging.2019.03.015","article-title":"Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer\u2019s disease and relationship to amyloid-\u03b2 and tau","volume":"80","author":"Jacobs","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Skorobogatov, K., De Picker, L., Verkerk, R., Coppens, V., Leboyer, M., M\u00fcller, N., and Morrens, M. (2021). Brain Versus Blood: A Systematic Review on the Concordance Between Peripheral and Central Kynurenine Pathway Measures in Psychiatric Disorders. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.716980"},{"key":"ref_59","first-page":"1059","article-title":"Anthranilic Acid: A Potential Biomarker and Treatment Target for Schizophrenia","volume":"4","author":"Oxenkrug","year":"2016","journal-title":"Ann. Psychiatry Ment. Health"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Fazio, F., Lionetto, L., Curto, M., Iacovelli, L., Cavallari, M., Zappulla, C., Ulivieri, M., Napoletano, F., Capi, M., and Corigliano, V. (2015). Xanthurenic acid activates mGlu2\/3 metabotropic glutamate receptors and is a potential trait marker for schizophrenia. Sci. Rep., 5.","DOI":"10.1038\/srep17799"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.schres.2022.01.048","article-title":"Gender-specific elevation of plasma anthranilic acid in schizophrenia: Protection against glutamatergic hypofunction?","volume":"243","author":"Steiner","year":"2022","journal-title":"Schizophr. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11786469241239125","DOI":"10.1177\/11786469241239125","article-title":"Anthranilic Acid, a GPR109A Agonist, and Schizophrenia","volume":"17","author":"Oxenkrug","year":"2024","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.jalz.2017.04.009","article-title":"Association of amine biomarkers with incident dementia and Alzheimer\u2019s disease in the Framingham Study","volume":"13","author":"Chouraki","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chatterjee, P., Goozee, K., Lim, C.K., James, I., Shen, K., Jacobs, K.R., Sohrabi, H.R., Shah, T., Asih, P.R., and Dave, P. (2018). Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-\u03b2 load: A pilot study. Sci. Rep., 22.","DOI":"10.1038\/s41598-018-25968-7"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"120819","DOI":"10.1016\/j.jns.2023.120819","article-title":"The role of the kynurenine pathway in cognitive functioning after stroke: A prospective clinical study","volume":"454","author":"Bakker","year":"2023","journal-title":"J. Neurol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1111\/j.1432-1033.1996.0460u.x","article-title":"Isolation and expression of a cDNA clone encoding human kynureninase","volume":"239","author":"Buchli","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_67","first-page":"179","article-title":"Vergleich der Kynureninase-Aktivit\u00e4t in verschiedenen Organen von S\u00e4ugetieren [Comparison of kynureninase activity in various organs of mammals]","volume":"29","author":"Machill","year":"1972","journal-title":"Acta Biol. Med. Ger."},{"key":"ref_68","unstructured":"Georgiou, G., Stern, E., Blazek, J., and Calamito, C. (2023). Human Kynureninase Enzymes and Uses Thereof. (11,648,272 B2), U.S. Patent."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nbt.4180","article-title":"Reversal of IDO-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme","volume":"36","author":"Triplett","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1042\/bj3260351","article-title":"Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types","volume":"326","author":"Heyes","year":"1997","journal-title":"Biochem. J."},{"key":"ref_71","first-page":"996","article-title":"Regulation of the kynurenine metabolic pathway by interferon-y in murine cloned macrophages microglial cells","volume":"66","author":"Kohler","year":"1996","journal-title":"J. Neu-Rochem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1476-9255-8-25","article-title":"Effects of pro-inflammatory cytokines on expression of kynurenine pathway enzymes in human dermal fibroblasts","volume":"8","author":"Asp","year":"2011","journal-title":"J. Inflamm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S0165-5728(01)00418-0","article-title":"Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages","volume":"120","author":"Chiarugi","year":"2001","journal-title":"J. Neuroimmunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E166","DOI":"10.1503\/jpn.190139","article-title":"The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-\u03b12a and oral ribavirin","volume":"46","author":"Pawlowski","year":"2021","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ymgme.2014.11.010","article-title":"Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans","volume":"114","author":"Burton","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1128\/jb.160.2.651-655.1984","article-title":"Anthranilate Hydroxylase from Aspergillus niger: New Type of NADPH-Linked Nonheme Iron Monooxygenase","volume":"160","author":"Subramanian","year":"1984","journal-title":"J. Bacteriol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.biopsych.2013.08.010","article-title":"Benzoate, a D-Amino Acid Oxidase Inhibitor, for the Treatment of Early-Phase Alzheimer Disease: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"75","author":"Lin","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1001\/jamapsychiatry.2013.2159","article-title":"Add-on Treatment of Benzoate for Schizophrenia. A Randomized, Double-blind, Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor","volume":"70","author":"Lane","year":"2013","journal-title":"JAMA Psychiatry"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1021\/ml200204m","article-title":"Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia","volume":"3","author":"Dounay","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"36554","DOI":"10.1074\/jbc.M113.503813","article-title":"Targeted deletion of kynurenine 3-monooxygenase in mice: A new tool for studying kynurenine pathway metabolism in periphery and brain","volume":"288","author":"Giorgini","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Phillips, R.S., Iradukunda, E.C., Hughes, T., and Bowen, J.P. (2019). Modulation of Enzyme Activity in the Kynurenine Pathway by Kynurenine Monooxygenase Inhibition. Front. Mol. Biosci., 6.","DOI":"10.3389\/fmolb.2019.00003"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cccn.2005.04.013","article-title":"The effect of age on the enzyme activities of tryptophan metabolism along the kynurenine pathway in rats","volume":"360","author":"Comai","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.yebeh.2014.06.001","article-title":"The effects of vagus nerve stimulation on tryptophan metabolites in children with intractable epilepsy","volume":"37","author":"Klinkenberg","year":"2014","journal-title":"Epilepsy Behav."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Olsen, L.K., Solis, E., McIntire, L.K., and Hatcher-Solis, C.N. (2023). Vagus nerve stimulation: Mechanisms and factors involved in memory enhancement. Front. Hum. Neurosci., 17.","DOI":"10.3389\/fnhum.2023.1152064"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1365-2796.2005.01528.x","article-title":"Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary review","volume":"258","author":"Carlson","year":"2005","journal-title":"J. Intern. Med."},{"key":"ref_86","first-page":"763","article-title":"Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain","volume":"18","author":"Taing","year":"2013","journal-title":"Neur Regen. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"148ra115","DOI":"10.1126\/scitranslmed.3003877","article-title":"Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression","volume":"4","author":"Lauring","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/cpdd.704","article-title":"A randomized, placebo-controlled trial to assess the effects of 8 weeks of administration of GSK256073, a selective GPR109A agonist, on high-density lipoprotein cholesterol in subjects with dyslipidemia","volume":"8","author":"Olson","year":"2019","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/j.1365-2621.1966.tb15421.x","article-title":"Methyl Anthranilate Content of Citrus Honey","volume":"31","author":"White","year":"1996","journal-title":"J. Food Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1051\/apido:2008009","article-title":"Methyl anthranilate in Citrus honey. Analytical method and suitability as a chemical marker","volume":"39","author":"Sesta","year":"2008","journal-title":"Apidologie"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00726-008-0031-z","article-title":"Presence of kynurenic acid in food and honeybee products","volume":"36","author":"Turski","year":"2009","journal-title":"Amino Acids"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jfca.2016.02.003","article-title":"An exceptionally high content of kynurenic acid in chestnut honey and flowers of chestnut tree","volume":"48","author":"Turski","year":"2016","journal-title":"J. Food Compos. Analysis"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Hughes, C.F., Ward, M., Tracey, F., Hoey, L., Molloy, A.M., Pentieva, K., and McNulty, H. (2017). B-Vitamin Intake and Biomarker Status in Relation to Cognitive Decline in Healthy Older Adults in a 4-Year Follow-Up Study. Nutrients, 9.","DOI":"10.3390\/nu9010053"},{"key":"ref_94","unstructured":"Caballero, B. (2013). Vitamin B6: Physiology. Encyclopedia of Human Nutrition, Academic Press. [3rd ed.]."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e216156","DOI":"10.1001\/jamanetworkopen.2021.6156","article-title":"Effect of Sodium Benzoate on Cognitive Function among Patients with Behavioral and Psychological Symptoms of Dementia. Secondary Analysis of a Randomized Clinical Trial","volume":"4","author":"Lin","year":"2021","journal-title":"JAMA Netw. Open."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Jayawickrama, G.S., Nematollahi, A., Sun, G., Gorrell, M.D., and Church, W.B. (2017). Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17979-7"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0165-1781(89)90031-0","article-title":"Correlation between brain adrenal axis activity and cognitive impairment in Alzheimer\u2019s disease: Is there a gender effect?","volume":"29","author":"Oxenkrug","year":"1989","journal-title":"Psychiatry Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"743","DOI":"10.2466\/pr0.2002.91.3.743","article-title":"Sex differences in cerebral tissue volume and cognitive performance during adolescence","volume":"91","author":"Killgore","year":"2002","journal-title":"Psychol. Rep."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1056\/NEJMe2400102","article-title":"Alzheimer\u2019s disease biomarkers\u2014Timing is everything","volume":"390","author":"Mayeux","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Rabbito, A., Dulewicz, M., Kulczy\u0144ska-Przybik, A., and Mroczko, B. (2020). Biochemical Markers in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061989"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/0020-711X(71)90065-6","article-title":"Tryptophan metabolism in baboons: Effect of riboflavin and pyridoxine deficiency","volume":"2","author":"Verjee","year":"1973","journal-title":"Intern. J. Biochem."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Oxenkrug, G., van der Hart, M., Roeser, J., and Summergrad, P. (2017). Peripheral Tryptophan\u2014Kynurenine Metabolism Associated with Metabolic Syndrome is Different in Parkinson\u2019s and Alzheimer\u2019s Diseases. Endocrinol. Diabetes Metab. J., 1, Available online: http:\/\/researchopenworld.com\/wp-content\/uploads\/2017\/11\/EDMJ-2017-113.","DOI":"10.31038\/EDMJ.2017141"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2478\/v10039-010-0023-6","article-title":"Kynurenine and its metabolites in Alzheimer\u2019s disease patients","volume":"5","author":"Gulaj","year":"2010","journal-title":"Adv. Med. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.schres.2010.03.025","article-title":"Niacin sensitivity and the arachidonic acid pathway in schizophrenia","volume":"122","author":"Messamore","year":"2010","journal-title":"Schizophr. Res."},{"key":"ref_105","first-page":"988","article-title":"Niacin-respondent subset of schizophrenia\u2014A therapeutic review","volume":"19","author":"Xu","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13269\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:51:49Z","timestamp":1760115109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,10]]},"references-count":105,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413269"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413269","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,10]]}}}