Sex-specific Associations Between Serum Quinolinic Acid and Disease Severity in Relapsing-remitting Multiple Sclerosis: A Cross-sectional Study

  • Marija Vasić Military Medical Academy – Institute of Medical Biochemistry, Belgrade, Serbia
Keywords: multiple sclerosis, kynurenine pathway, kynurenine acid, quinolinic acid, sex differences, disease severity

Abstract


The kynurenine pathway (KP) of tryptophan metabolism generates metabolites with both neuroprotective and neurotoxic properties and has been implicated in multiple sclerosis (MS). However, the relationship between KP metabolites, disease severity, and sex remains unclear. Serum levels of quinolinic acid (QA) and kynurenic acid (KA) were analyzed in a cohort of patients with relapsing-remitting MS. Of the 78 initially recruited patients, biomarker data were available for 40 patients, who were included in the final analysis. Disease severity was assessed using the Multiple Sclerosis Severity Score (MSSS) and patients were stratified into mild-to-moderate (MSSS < 6.7) and a severe disease group. Serum QA and KA concentrations were measured by the enzyme-linked immunosorbent assay (ELISA) and analyzed using two-way ANOVA with Sidak post hoc correction. No significant overall sex-related differences in serum QA or KA levels were observed. KA levels did not differ across MSSS categories. Female patients with high disease severity (MSSS > 6.7) exhibited higher serum QA levels compared with those with lower disease severity (p = 0.032), although this finding was observed in a very small subgroup of female patients (n = 3). These findings suggest a possible sex-related association between elevated serum QA levels and greater disease severity in female patients with RRMS and warrant confirmation in larger studies.

References

Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4:43. doi: 10.1038/s41572-018-0050-3.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52. doi: 10.1212/wnl.33.11.1444.

Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, et al. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005;64:1144–51. doi: 10.1212/01.WNL.0000156155.19270.F8.

Schwarcz R, Stone TW. The kynurenine pathway and the brain. Neuropharmacology. 2017;112:237–47. doi: 10.1016/j.neuropharm.2016.08.003.

Rajda C, Galla Z, Polyák H, Maróti Z, Babarczy K, Pukoli D, et al. Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis. Int J Mol Sci. 2020;21:2665. doi: 10.3390/ijms21082665.

Sundaram G, Brew BJ, Jones SP, Adams S, Lim CK, Guillemin GJ. Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. J Neuroinflammation. 2014;11:204. doi: 10.1186/s12974-014-0204-5.

Füvesi J, Rajda C, Bencsik K, Toldi J, Vécsei L. The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications. J Neural Transm. 2012;119:225–34. doi: 10.1007/s00702-012-0765-3.

Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012;279:1356–65. doi: 10.1111/j.1742-4658.2012.08485.x.

Yan J, Kothur K, Mohammad S, Chung J, Patel S, Jones HF, et al. CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation. EBioMedicine. 2023;91:104589. doi: 10.1016/j.ebiom.2023.104589.

Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25:131–47. doi: 10.1038/s41380-019-0414-4.

Voskuhl RR. The effect of sex on multiple sclerosis risk and disease progression. Mult Scler. 2020;26:554–60. doi: 10.1177/1352458519892491.

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–73. doi: 10.1016/S1474-4422(17)30470-2.

Stone TW, Stoy N, Darlington LG. An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci. 2013;34:136–43. doi: 10.1016/j.tips.2012.09.006.

Garrison AM, Parrott JM, Tuñon A, Delgado J, Redus L, O'Connor JC. Kynurenine pathway metabolic balance influences microglia activity: Targeting kynurenine monooxygenase to dampen neuroinflammation. Psychoneuroendocrinology. 2018;94:1–10. doi: 10.1016/j.psyneuen.2018.04.019.

Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145:863–74. doi: 10.1016/j.cell.2011.05.020.

Published
2026/04/29
Section
Original scientific paper