The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

• Published in: Biomedicines Vol. 11; no. 3; p. 945
• Main Authors: Polyák, Helga, Galla, Zsolt, Nánási, Nikolett, Cseh, Edina Katalin, Rajda, Cecília, Veres, Gábor, Spekker, Eleonóra, Szabó, Ágnes, Klivényi, Péter, Tanaka, Masaru, Vécsei, László
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Animal models; Animals; Anthranilic acid; Apoptosis; Autopsy; Body weight; Brain research; Cerebrospinal fluid; Cuprizone; Demyelination; Disease; Encephalomyelitis; High-performance liquid chromatography; Intoxication; Kynurenic acid; kynurenine; Mass spectroscopy; Medical research; Metabolism; Metabolites; Multiple sclerosis; Myelination; Nervous system; Neurodegeneration; Oxidative stress; Physiological aspects; PPMS; SPMS; Tryptophan; Xanthurenic acid; Hungary; cuprizone; PPMS; translational; SPMS; demyelination; multiple sclerosis; kynurenine; animal model; tryptophan; remyelination
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11030945

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.