{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T03:13:38Z","timestamp":1762053218317,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and\/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on the cerebrospinal fluid (CSF) metabolome in a murine model of AKU, with a view to providing additional insight into metabolic changes that occur following treatment with nitisinone. Methods: 17 CSF samples were collected from BALB\/c Hgd\u2212\/\u2212 mice (n = 8, treated with nitisinone\u20144 mg\/L and n = 9, no treatment). Samples were diluted 1:1 with deionised water and analysed using a 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, Cheadle, UK). Raw data were processed using a targeted feature extraction algorithm and an established in-house accurate mass retention time database. Matched entities (\u00b110 ppm theoretical accurate mass and \u00b10.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini\u2013Hochberg false-discovery rate adjustment. Results: L-Tyrosine, N-acetyl-L-tyrosine, \u03b3-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6\u20136.9, 3\/5 were significant p &lt; 0.05) in the mice that received nitisinone. Several other metabolites of interest were matched, but no significant differences were observed, including the aromatic amino acids phenylalanine and tryptophan, and monoamine metabolites adrenaline, 3-methoxy-4-hydroxyphenylglycol, and octopamine. Conclusions: Evaluation of the CSF metabolome of a murine model of AKU revealed a significant increase in the abundance of a limited number of metabolites following treatment with nitisinone. Further work is required to understand the significance of these findings and the mechanisms by which the altered metabolite abundances occur.<\/jats:p>","DOI":"10.3390\/metabo12060477","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:14:14Z","timestamp":1653437654000},"page":"477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5501-4475","authenticated-orcid":false,"given":"Andrew S.","family":"Davison","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Liverpool L69 3GA, UK"},{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan P.","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hazel","family":"Sutherland","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"},{"name":"School of Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M.","family":"Milan","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Liverpool L69 3GA, UK"},{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-6279","authenticated-orcid":false,"given":"Jonathan C.","family":"Jarvis","sequence":"additional","affiliation":[{"name":"School of Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lakshminarayan R.","family":"Ranganath","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Liverpool University Hospitals NHS Foundation Trust, Liverpool L69 3GA, UK"},{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1056\/NEJMoa021736","article-title":"Natural History of Alkaptonuria","volume":"347","author":"Phomphutkul","year":"2002","journal-title":"N. 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