Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria

Davison, Andrew S ORCID: 0000-0001-5501-4475, Norman, Brendan P ORCID: 0000-0001-9293-4852, Sutherland, Hazel, Milan, Anna M, Gallagher, James A ORCID: 0000-0002-0852-279X, Jarvis, Jonathan C and Ranganath, Lakshminarayan R
(2022) Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria. METABOLITES, 12 (6). 477-.

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<h4>Background</h4>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.<h4>Methods</h4>17 CSF samples were collected from BALB/c <i>Hgd</i><sup>-/-</sup> mice (<i>n</i> = 8, treated with nitisinone-4 mg/L and <i>n</i> = 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 (±10 ppm theoretical accurate mass and ±0.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini-Hochberg false-discovery rate adjustment.<h4>Results</h4>L-Tyrosine, N-acetyl-L-tyrosine, γ-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6-6.9, 3/5 were significant <i>p</i> &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.<h4>Conclusions</h4>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.

Item Type: Article
Uncontrolled Keywords: Alkaptonuria, hypertyrosinaemia, neurotransmitters, cognitive function
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 04 Nov 2022 12:53
Last Modified: 18 Jan 2023 19:43
DOI: 10.3390/metabo12060477
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