{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:06:29Z","timestamp":1784293589844,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006181","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado da Bahia","doi-asserted-by":"publisher","award":["BOL0284\/2020"],"award-info":[{"award-number":["BOL0284\/2020"]}],"id":[{"id":"10.13039\/501100006181","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["EU-Process No. 407833\/2023-4"],"award-info":[{"award-number":["EU-Process No. 407833\/2023-4"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["PI SLC Fellowship 312388\/2021-7"],"award-info":[{"award-number":["PI SLC Fellowship 312388\/2021-7"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cells in the central nervous system (CNS) can adapt to injury and inflammation through structural and functional changes, many of which are mediated by the kynurenine pathway (KP). Studies using glia\u2013neuron co-cultures showed that the biflavonoid agathisflavone (FAB), purified from the leaves of Cenostigma pyramidale Tul., a plant native to the Brazilian caatinga, exerts strong neuroprotective effects. This study evaluated whether agathisflavone (1 \u00b5M) modulates these responses in human and murine astrocytes and microglia exposed to inflammatory activation with lipopolysaccharide (LPS, 1 \u00b5g\/mL), excitotoxic activation of NMDA receptors with quinolinic acid (QUIN, 500 \u00b5M), or inhibition of the KP rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with 1-methyl tryptophan (1-MT, 1.5 \u03bcM). Co-treatment with FAB increased astrocyte viability relative to LPS, QUIN, or 1-MT alone, by up to 35% (p &lt; 0.05), while reducing GFAP overexpression and other features of reactive astrogliosis. FAB decreased the proportion of Iba-1+ microglia, indicating anti-inflammatory effects. When combined with QUIN or 1-MT, FAB reversed the elevation of iNOS (p &lt; 0.0001) and reduced IL1\u03b2 upregulation. FAB also modulated KP activity in a cell type-specific manner. In astrocytes, FAB with QUIN or with 1-MT increased IDO activity, whereas in microglia, FAB alone reduced it. In microglia, kynurenine-3-monooxygenase (KMO) expression was significantly increased under FAB+QUIN or FAB+1-MT (p &lt; 0.0001). Finally, astrocyte-conditioned medium from FAB-treated cells increased the viability of neuron-like PC12 cells by up to 40%. Collectively, these findings show that FAB confers cytoprotective and anti-inflammatory actions on glial cells, modulates KP signalling in a context-dependent manner, and supports neuronal survival under neuroinflammatory conditions.<\/jats:p>","DOI":"10.3390\/ijms262411951","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T14:30:17Z","timestamp":1765463417000},"page":"11951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Agathisflavone Modulates the Kynurenine Pathway and Glial Inflammatory Responses with Implications for Neuroprotection"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1186-3429","authenticated-orcid":false,"given":"Deivison Silva","family":"Argolo","sequence":"first","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4876-5566","authenticated-orcid":false,"given":"Lucas Matheus Gon\u00e7alves","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6428-4485","authenticated-orcid":false,"given":"Cleonice Creusa dos","family":"Santos","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4469-3862","authenticated-orcid":false,"given":"Lilian Vanessa","family":"da Penha Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7926-795X","authenticated-orcid":false,"given":"Erick Correia","family":"Loiola","sequence":"additional","affiliation":[{"name":"Center of Biotechnology and Cell Therapy, S\u00e3o Rafael Hospital, D\u2019Or Institute for Research and Education (IDOR), Av. S\u00e3o Rafael, 2152-S\u00e3o Rafael, Salvador 41253-190, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno Solano","family":"de Freitas Souza","sequence":"additional","affiliation":[{"name":"Center of Biotechnology and Cell Therapy, S\u00e3o Rafael Hospital, D\u2019Or Institute for Research and Education (IDOR), Av. S\u00e3o Rafael, 2152-S\u00e3o Rafael, Salvador 41253-190, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Barreto","sequence":"additional","affiliation":[{"name":"Neuroendocrine Pharmacology Lab, Department of Biological Sciences, Faculty of Science and Engineering, University of Limerick, V94 T9PX Limerick, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7579-0746","authenticated-orcid":false,"given":"Arthur Morgan","family":"Butt","sequence":"additional","affiliation":[{"name":"School of Medicine, Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6375-9055","authenticated-orcid":false,"given":"Jorge Mauricio","family":"David","sequence":"additional","affiliation":[{"name":"Department of General and Inorganic Chemistry, Institute of Chemistry, University Federal da Bahia, Salvador 40170-110, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexsandro","family":"Branco","sequence":"additional","affiliation":[{"name":"Laboratory of Phytochemistry, Department of Health, State University of Feira de Santana, Av. Transnordestina, s\/n, Feira de Santana 44036-900, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-3347","authenticated-orcid":false,"given":"Isabella Mary Alves","family":"Reis","sequence":"additional","affiliation":[{"name":"Laboratory of Phytochemistry, Department of Health, State University of Feira de Santana, Av. Transnordestina, s\/n, Feira de Santana 44036-900, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Azevedo-Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Phytochemistry, Department of Health, State University of Feira de Santana, Av. Transnordestina, s\/n, Feira de Santana 44036-900, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8975-3871","authenticated-orcid":false,"given":"Silvia Lima","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"},{"name":"National Institute of Translational Neuroscience (INCT-CNPq), Federal University of Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0916-2893","authenticated-orcid":false,"given":"Maria de F\u00e1tima Dias","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Neurochemistry and Cellular Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon S\/N, Salvador 40231-300, BA, Brazil"},{"name":"National Institute of Translational Neuroscience (INCT-CNPq), Federal University of Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1046\/j.1471-4159.2001.00498.x","article-title":"Kynurenine pathway metabolism in human astrocytes: A paradox for neuronal protection","volume":"78","author":"Guillemin","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/glia.10175","article-title":"Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes","volume":"41","author":"Guillemin","year":"2003","journal-title":"Glia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0031-6997(25)00441-7","article-title":"Neuropharmacology of quinolinic and kynurenic acids","volume":"45","author":"Stone","year":"1993","journal-title":"Pharmacol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, Y., Wang, W., Zhang, Y., Dong, X., and Liu, Y. (2025). Diverse physiological roles of kynurenine pathway metabolites: Updated implications for health and disease. Metabolites, 15.","DOI":"10.3390\/metabo15030210"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1124\/pharmrev.124.000239","article-title":"Neuroactive kynurenines as pharmacological targets: New experimental tools and exciting therapeutic opportunities","volume":"76","author":"Pocivavsek","year":"2024","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.neuropharm.2016.01.011","article-title":"L-Tryptophan\u2013kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences","volume":"112","author":"Fujigaki","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1111\/j.1742-4658.2012.08485.x","article-title":"Quinolinic acid, the inescapable neurotoxin","volume":"279","author":"Guillemin","year":"2012","journal-title":"FEBS J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1042\/bj2830633","article-title":"Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid","volume":"283","author":"Heyes","year":"1992","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Heylen, A., Vermeiren, Y., Kema, I.P., van Faassen, M., van der Ley, C., Van Dam, D., and De Deyn, P.P. (2023). Brain kynurenine pathway metabolite levels may reflect extent of neuroinflammation in ALS, FTD and early onset AD. Pharmaceuticals, 16.","DOI":"10.3390\/ph16040615"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100584","DOI":"10.1016\/j.bbih.2022.100584","article-title":"Kynurenine pathway abnormalities are state-specific but not diagnosis-specific in schizophrenia and bipolar disorder","volume":"27","author":"Skorobogatov","year":"2023","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Stone, T.W., Clanchy, F.I.L., Huang, Y.S., Chiang, N.Y., Darlington, L.G., and Williams, R.O. (2022). An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1002004"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.drudis.2021.02.009","article-title":"Inflammation control and improvement of cognitive function in COVID-19 infections: Is there a role for kynurenine 3-monooxygenase inhibition?","volume":"26","author":"Collier","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0014-2999(88)90367-6","article-title":"Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor","volume":"154","author":"Birch","year":"1988","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuint.2019.02.001","article-title":"Linking phencyclidine intoxication to the tryptophan\u2013kynurenine pathway: Therapeutic implications for schizophrenia","volume":"125","author":"Fujigaki","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.neuro.2018.02.001","article-title":"Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity","volume":"65","author":"Souza","year":"2018","journal-title":"Neurotoxicology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"de Almeida, M.M.A., Souza, C.d.S., Dourado, N.S., da Silva, A.B., Ferreira, R.S., David, J.M., David, J.P., Costa, M.d.F.D., da Silva, V.D.A., and Butt, A.M. (2020). Phytoestrogen agathisflavone ameliorates neuroinflammation induced by LPS and IL-1\u03b2 and protects neurons in cocultures of glia\/neurons. Biomolecules, 10.","DOI":"10.3390\/biom10040562"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s11481-021-09991-6","article-title":"Agathisflavone modifies microglial activation state and myelination in organotypic cerebellar slices culture","volume":"17","author":"Pieropan","year":"2022","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"dos Santos, B.L., dos Santos, C.C., Soares, J.R.P., da Silva, K.C., de Oliveira, J.V.R., Pereira, G.S., de Ara\u00fajo, F.M., Costa, M.d.F.D., David, J.M., and da Silva, V.D.A. (2023). The flavonoid agathisflavone directs brain microglia\/macrophages to a neuroprotective anti-inflammatory and antioxidant state via regulation of NLRP3 inflammasome. Pharmaceutics, 15.","DOI":"10.1016\/j.ibneur.2023.08.474"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"do Nascimento, R.P., dos Santos, B.L., Amparo, J.A.O., Soares, J.R.P., da Silva, K.C., Santana, M.R., Almeida, \u00c1.M.A.N., da Silva, V.D.A., Costa, M.d.F.D., and Ulrich, H. (2022). Neuroimmunomodulatory properties of flavonoids and derivates: A potential action as adjuvants for the treatment of glioblastoma. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010116"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"149310","DOI":"10.1016\/j.brainres.2024.149310","article-title":"Cellular stress response and neuroprotection of flavonoids in neurodegenerative diseases: Clinical insights into targeted therapy and molecular signaling pathways","volume":"1847","author":"Utpal","year":"2025","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1742-2094-6-36","article-title":"Effect of quinolinic acid on human astrocytes morphology and functions: Implications in Alzheimer\u2019s disease","volume":"6","author":"Ting","year":"2009","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kim, S., and Son, Y. (2021). Astrocytes stimulate microglial proliferation and M2 polarization in vitro through crosstalk between astrocytes and microglia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168800"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s12035-008-8043-y","article-title":"Targeted activation of astrocytes: A potential neuroprotective strategy","volume":"38","author":"Escartin","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hasan, S., Khatri, N., Rahman, Z.N., Menezes, A.A., Martini, J., Shehjar, F., Mujeeb, N., and Shah, Z.A. (2023). Neuroprotective potential of flavonoids in brain disorders. Brain Sci., 13.","DOI":"10.3390\/brainsci13091258"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4137\/IJTR.S12626","article-title":"The kynurenine pathway in stem cell biology","volume":"6","author":"Jones","year":"2013","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.neuropharm.2016.03.024","article-title":"Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases","volume":"112","author":"Lovelace","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/glia.20090","article-title":"Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons","volume":"49","author":"Guillemin","year":"2005","journal-title":"Glia"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pathak, S., Nadar, R., Kim, S., Liu, K., Govindarajulu, M., Cook, P., Alexander, C.S.W., Dhanasekaran, M., and Moore, T. (2024). The influence of kynurenine metabolites on neurodegenerative pathologies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25020853"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.tins.2010.12.001","article-title":"Astrocyte\u2013neuron metabolic relationships: For better and for worse","volume":"34","author":"Allaman","year":"2011","journal-title":"Trends Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41392-023-01628-9","article-title":"Astrocytes in human central nervous system diseases: A frontier for new therapies","volume":"8","author":"Verkhratsky","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.vetpar.2019.01.003","article-title":"IDO, COX and iNOS have an important role in the proliferation of Neospora caninum in neuron\/glia co-cultures","volume":"266","author":"Jesus","year":"2019","journal-title":"Vet. Parasitol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e70006","DOI":"10.1111\/ppl.70006","article-title":"Exogenous melatonin improves drought stress tolerance via regulating tryptophan metabolism and flavonoid biosynthesis pathways in wheat","volume":"176","author":"Li","year":"2024","journal-title":"Physiol. Plant."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Santana, M.R., Santos, Y.B., Santos, K.S., Santos, M.C.J., Victor, M.M., Ramos, G.S., Nascimento, R.P.D., and Costa, S.L. (2024). Differential interactions of flavonoids with the aryl hydrocarbon receptor in silico and their impact on receptor activity in vitro. Pharmaceuticals, 17.","DOI":"10.3390\/ph17080980"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s41380-022-01830-1","article-title":"Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization","volume":"28","author":"Trindade","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Miranda-Negr\u00f3n, Y., and Garc\u00eda-Arrar\u00e1s, J.E. (2022). Radial glia and radial glia-like cells: Their role in neurogenesis and regeneration. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1006037"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s12974-023-02856-0","article-title":"Emerging role of non-coding RNAs in neuroinflammation mediated by microglia and astrocytes","volume":"20","author":"Yang","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yoon, H., Walters, G., Paulsen, A.R., and Scarisbrick, I.A. (2017). Astrocyte heterogeneity across the brain and spinal cord occurs developmentally, in adulthood and in response to demyelination. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180697"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Mithaiwala, M.N., Geiger, J.D., and Gendelman, H.E. (2021). Neuroinflammation and the kynurenine pathway in CNS disease. Cells, 10.","DOI":"10.3390\/cells10061548"},{"key":"ref_40","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":"2016","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1111\/bph.12230","article-title":"The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders","volume":"169","author":"Stone","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Campbell, B.M., White, A.M., and McCauley, M.E. (2014). Kynurenines in CNS disease: Regulation by inflammatory cytokines. Front. Neurosci., 8.","DOI":"10.3389\/fnins.2014.00012"},{"key":"ref_43","first-page":"1","article-title":"Glial and tissue-specific regulation of kynurenine pathway metabolism","volume":"8","author":"Dostal","year":"2017","journal-title":"Adv. Neuroimmune Biol."},{"key":"ref_44","first-page":"46","article-title":"Kynurenine metabolic balance is disrupted in the brain and blood of socially stressed rats: A possible mechanistic link to depression","volume":"13","author":"Parrott","year":"2016","journal-title":"J. Neuroinflamm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11951\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T05:17:18Z","timestamp":1765603038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/11951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":44,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262411951"],"URL":"https:\/\/doi.org\/10.3390\/ijms262411951","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]}}}