Citation: Polyák, H.; Galla, Z.; Nánási, N.; Cseh, E.K.; Rajda, C.; Veres, G.; Spekker, E.; Szabó, Á.; Klivényi, P.; Tanaka, M.; et al. The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone- Induced Model of Demyelination Simulating Progressive Multiple Sclerosis. Biomedicines 2023, 11, 945. https://doi.org/10.3390/ biomedicines11030945 Academic Editors: David R. Wallace and Víctor M. Rivera Received: 17 January 2023 Revised: 7 March 2023 Accepted: 16 March 2023 Published: 20 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biomedicines Article The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis Helga Polyák 1,2 , Zsolt Galla 3 , Nikolett Nánási 4 , Edina Katalin Cseh 1 , Cecília Rajda 1 ,Gábor Veres 5 , Eleonóra Spekker 4 , Ágnes Szabó 1,2 ,Péter Klivényi 1 , Masaru Tanaka 4,† and László Vécsei 1,4, * ,† 1 Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary; polyak.helga@med.u-szeged.hu (H.P.); cseh.edina@med.u-szeged.hu (E.K.C.); rajda.cecilia@med.u-szeged.hu (C.R.); szabo.agnes.4@med.u-szeged.hu (Á.S.); peter.klivenyi@med.u-szeged.hu (P.K.) 2 Doctoral School of Clinical Medicine, University of Szeged, Korányi fasor 6, H-6720 Szeged, Hungary 3 Department of Pediatrics, Albert Szent-Györgyi Faculty of Medicine, University of Szeged, H-6725 Szeged, Hungary; galla.zsolt@med.u-szeged.hu 4 Danube Neuroscience Research Laboratory, ELKH-SZTE Neuroscience Research Group, Eötvös Loránd Research Network, University of Szeged (ELKH-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary; nannik1026@gmail.com (N.N.); spekker.eleonora@gmail.com (E.S.); tanaka.masaru.1@med.u-szeged.hu (M.T.) 5 Independent Researcher, H-6726 Szeged, Hungary; weresdzsi@gmail.com * Correspondence: vecsei.laszlo@med.u-szeged.hu; Tel.: +36-62-545-351 † These authors contributed equally to this work. Abstract: Progressive multiple sclerosis (MS) is a chronic disease with a unique pattern, which is histologically classified into the subpial type 3 lesions in the autopsy. The lesion is also homologous to that of cuprizone (CPZ) toxin-induced animal models of demyelination. Aberration of the tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed in patients with MS; nevertheless, the KYN metabolite profile of progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated with 0.2% CPZ toxin for 5 weeks and then underwent 4 weeks of recovery. We measured the levels of serotonin, TRP, and KYN metabolites in the plasma and the brain samples of mice at weeks 1, 3, and 5 of demyelination, and at weeks 7 and 9 of remyelination periods by ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement and immunohistochemical analysis to confirm the development of demyelination. The UHPLC-MS/MS measurements demonstrated a significant reduction of kynurenic acid, 3-hydoxykynurenine (3-HK), and xanthurenic acid in the plasma and a significant reduction of 3-HK, and anthranilic acid in the brain samples at week 5. Here, we show the profile of KYN metabolites in the CPZ-induced mouse model of demyelination. Thus, the KYN metabolite profile potentially serves as a biomarker of progressive MS and thus opens a new path toward planning personalized treatment, which is frequently obscured with immunologic components in MS deterioration. Keywords: multiple sclerosis; PPMS; SPMS; tryptophan; kynurenine; cuprizone; demyelination; remyelination; animal model; translational 1. Introduction Multiple sclerosis (MS) is an inflammatory, neurodegenerative, and immune-mediated disorder of the central nervous system (CNS), which is characterized by the appearance of inflammatory lesions of the white matter, axonal damage, loss of oligodendrocyte and axons, gliosis, demyelination, as well as neurodegeneration [1–5]. MS is still an incurable disease and is estimated to affect 2.8 million people worldwide [6]. It occurs most often in one of the most productive stages of life, i.e., in young adulthood, which makes the disease Biomedicines 2023, 11, 945. https://doi.org/10.3390/biomedicines11030945 https://www.mdpi.com/journal/biomedicines