Original Scientific Article
1H-NMR analysis of amino acid metabolism in cerebrospinal fluid of dogs with neurological distemper
Erdem Gülersoy * ,
Canberk Balikçi ,
Ismail Günal ,
Adem Şahan ,
Esma Kismet ,
Fatma Akdağ ,
Mahmut Ok

Mac Vet Rev 2024; 47 (2): 131 - 140

10.2478/macvetrev-2024-0024

Received: 16 March 2024

Received in revised form: 13 August 2024

Accepted: 15 August 2024

Available Online First: 30 August 2024

Published on: 15 October 2024

Correspondence: Erdem Gülersoy, egulersoy@harran.edu.tr
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Abstract

Canine Distemper Virus (CDV) infection causes a multifocal demyelinating progressive disease within the central nervous system (CNS) that results in wide range of neurological symptoms. Pathological changes in the brain or CNS could be observed by analyzing cerebrospinal fluid (CSF). Therefore, this study aimed to investigate the concentrations of amino acids in the CSF of dogs with neurological form of CDV infection, and to identify amino acids as markers that can be used in the diagnosis, pathogenesis, and treatment of the disease. Heathy dogs (n=6), confirmed by clinical and laboratory examinations (Healthy group), and CDV-infected dogs (n=10) with neurological symptoms, confirmed by clinical, laboratory, and rapid diagnostic test kits (Distemper group), were used. CSF samples were obtained with an appropriate method and were subjected to 1H-NMR analysis. Identification was made on 10, whereas quantification on 8 amino acids. L-tyrosine, L-phenylalanine, L-threonine, and L-alanine concentrations were significantly lower, while L-histidine and L-tryptophan were significantly higher than the Healthy group (p<0.05). It was concluded that L-tyrosine could be used for assessing mental status changes, L-phenylalanine for evaluating neuroprotective responses, L-threonine and L-histidine for gauging the extent of neurodegeneration and ventricular degeneration, L-alanine for exploring cellular stress and energy metabolism, and L-tryptophan for understanding the process of sympathetic nervous system activation.

Keywords: biomarker, dogs, NMR, CSF, amino acid

References

1. Lempp, C., Spitzbarth, I., Puff, C., Cana, A., Kegler, K., Techangamsuwan, S., Seehusen, F. (2014). New aspects of the pathogenesis of canine distemper leukoencephalitis. Viruses 6(7): 2571-2601. https://doi.org/10.3390/v6072571 PMid:24992230 PMCid:PMC4113784
2. Pratakpiriya, W., Seki, F., Otsuki, N., Sakai, K., Fukuhara, H., Katamoto, H., Lan, N. T. (2012). Nectin4 is an epithelial cell receptor for canine distemper virus and involved in the neurovirulence. J Virol. 86(18): 10207-10210. https://doi.org/10.1128/JVI.00824-12 PMid:22761370 PMCid:PMC3446623
3. Ludlow, M., Nguyen, D.T., Silin, D., Lyubomska, O., de Vries, R.D., von Messling, V., Duprex, W.P. (2012). Recombinant canine distemper virus strain Snyder Hill expressing green or red fluorescent proteins causes meningoencephalitis in the ferret. J Virol. 86(14): 7508-7519. https://doi.org/10.1128/JVI.06725-11 PMid:22553334 PMCid:PMC3416283
4. Amude, A.M., Alfieri, A.A., Alfieri, A.F. (2007). Clinicopathological findings in dogs with distemper encephalomyelitis presented without characteristic signs of the disease. Res Vet Sci. 82(3): 416-422. https://doi.org/10.1016/j.rvsc.2006.08.008 PMid:17084426
5. Ulrich, R., Puff, C., Wewetzer, K., Kalkuhl, A., Deschl, U., Baumgartner, W. (2014). Transcriptional changes in canine distemper virus-induced demyelinating leukoencephalitis favor a biphasic mode of demyelination. PLoS One 9(4): e95917. https://doi.org/10.1371/journal.pone.0095917 PMid:24755553 PMCid:PMC3995819
6. Smolinska, A., Blanchet, L., Buydens, L.M.C. Wijmenga, S.S. (2012). NMR and pattern recognition methods in metabolomics: From data acquisition to biomarker discovery: A review. Anal Chim Acta. 750, 82-97. https://doi.org/10.1016/j.aca.2012.05.049 PMid:23062430
7. Bechter, K. (2011). The peripheral cerebrospinal fluid outflow pathway physiology and pathophysiology of CSF recirculation: a review and hypothesis. Neurol Psychiatry Brain Res. 17(3): 51-66. https://doi.org/10.1016/j.npbr.2011.06.003 
8. Brunner, J.M., Plattet, P., Majcherczyk, P., Zurbriggen, A., Wittek, R., Hirling, H. (2007). Canine distemper virus infection of primary hippocampal cells induces an increase in extracellular glutamate and neurodegeneration. J Neurochem. 103(3): 1184-1195. https://doi.org/10.1111/j.1471-4159.2007.04819.x PMid:17680994
9. Cheng, J.Y., Deng, Y.T., Yu, J.T. (2023). The causal role of circulating amino acids in neurodegenerative disorders: a two-sample Mendelian randomization study. J Neurochem. 166(6): 972 981. https://doi.org/10.1111/jnc.15937 PMid:37565992
10. Liu, J., Li, S., Liu, J., Liang, B., Wang, X., Wang, H. (2020). Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 55, 102763. https://doi.org/10.1016/j.ebiom.2020.102763 PMid:32361250 PMCid:PMC7165294
11. Tipold, A. (2008). Cerebrospinal fluid. In: K.G. Braund (Ed.), Clinical neurology in Small Animals: Localization, Diagnosis and Treatment. New York, USA
12. Musteata, M., Nicolescu, A., Solcan, G., Deleanu, C. (2013). The 1H NMR profile of healthy dog cerebrospinal fluid. PLoS One 8(12): e81192. https://doi.org/10.1371/journal.pone.0081192 PMid:24376499 PMCid:PMC3871169
13. Ravanbakhsh, S., Liu, P., Bjorndahl, T.C., Mandal, R., Grant, J.R., Wilson, M. (2015). Accurate, fully-automated NMR spectral profiling for metabolomics. PloS One 10(5): e0124219. https://doi.org/10.1371/journal.pone.0124219 PMid:26017271 PMCid:PMC4446368
14. Galán, A., Gamito, A., Carletti, B.E., Guisado, A., de las Mulas, J.M., Pérez, J., Martín, E.M. (2014). Uncommon acute neurologic presentation of canine distemper in 4 adult dogs. Can Vet J. 55(4): 373-378.
15. Fairley, R.A., Knesl, O., Pesavento, P.A., Elias, B.C. (2015). Post-vaccinal distemper encephalitis in two Border Collie cross littermates. N Z Vet J. 63(2): 117-120. https://doi.org/10.1080/00480169.2014.955068 PMid:25120026
16. Noyce, R.S., Delpeut, S., Richardson, C.D. (2013). Dog nectin-4 is an epithelial cell receptor for canine distemper virus that facilitates virus entry and syncytia formation. Virology 436(1): 210-220. https://doi.org/10.1016/j.virol.2012.11.011 PMid:23260107
17. Vandevelde, M., Zurbriggen, A. (2005). Demyelination in canine distemper virus infection: a review. Acta Neuropathol. 109(1): 56-68. https://doi.org/10.1007/s00401-004-0958-4 PMid:15645260
18. Califf, R.M. (2018). Biomarker definitions and their applications. Exp Biol Med (Maywood). 243(3): 213-221. https://doi.org/10.1177/1535370217750088 PMid:29405771 PMCid:PMC5813875
19. Nicholson, J.K. (2006). Global systems biology, personalized medicine and molecular epidemiology. Mol Syst Biol. 2, 52. https://doi.org/10.1038/msb4100095 PMid:17016518 PMCid:PMC1682018
20. Lawrence, Y.A., Bishop, M.A., Honneffer, J.B., Cook, A.K., Rodrigues-Hoffmann, A., Steiner, J.M., Suchodolski, J.S., Lidbury, J.A. (2019). Untargeted metabolomic profiling of serum from dogs with chronic hepatic disease. J Vet Intern Med. 33(3): 1344-1352. https://doi.org/10.1111/jvim.15479 PMid:30891842 PMCid:PMC6524095
21. Constantinescu, R., Mondello, S. (2013). Cerebrospinal fluid biomarker candidates for Parkinsonian disorders. Front Neurol. 3, 187. https://doi.org/10.3389/fneur.2012.00187 PMid:23346074 PMCid:PMC3549487
22. Wishart, D.S., Lewis, M.J., Morrissey, J.A., Flegel, M.D., Jeroncic, K., Xiong, Y., Cheng, D., et al. (2008). The human cerebrospinal fluid metabolome. J Chromatogr B Analyt Technol Biomed Life Sci. 871(2): 164-173. https://doi.org/10.1016/j.jchromb.2008.05.001 PMid:18502700
23. Crews, B., Wikoff, W.R., Patti, G.J., Woo, H.K., Kalisiak, E. (2009). Variability analysis of human plasma and cerebral spinal fluid reveals statistical significance of changes in mass spectrometry-based metabolomics data. Anal Chem. 81(20): 8538-8544. https://doi.org/10.1021/ac9014947 PMid:19764780 PMCid:PMC3058611
24. Jongkees, B.J., Hommel, B., Kühn, S., Colzato, L.S. (2015). Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands--a review. J Psychiatr Res. 70, 50-57. https://doi.org/10.1016/j.jpsychires.2015.08.014 PMid:26424423
25. Dewey, C.W.A. (2008). Practical guide to canine and feline neurology. 2nd ed. Ames, Iowa, USA: Wiley-Blackwell
26. Glushakov, A.V., Dennis, D.M., Sumners, C., Seubert, C.N., Martynyuk, A.E. (2003). L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses. J Neurosci Res. 72(1): 116-124. https://doi.org/10.1002/jnr.10569 PMid:12645085
27. Kagiyama, T., Glushakov, A.V., Sumners, C., Roose, B., Dennis, D.M., Phillips, M.I., Ozcan, M.S., et al. (2004). Neuroprotective action of halogenated derivatives of L-phenylalanine. Stroke 35(5): 1192-1196. https://doi.org/10.1161/01.STR.0000125722.10606.07 PMid:15073406
28. López-Corcuera, B., Benito-Muñoz, C., Aragón, C. (2017). Glycine transporters in glia cells: structural studies. Adv Neurobiol. 16, 13-32. https://doi.org/10.1007/978-3-319-55769-4_2 PMid:28828604
29. Kaiser, E., Schoenknecht, P., Thomann, P.A., Hunt, A., Schroeder, J. (2007). Influence of delayed CSF storage on concentrations of phosphotau protein (181), total tau protein and beta amyloid (1-42). Neurosci Lett. 417(2): 193-195. https://doi.org/10.1016/j.neulet.2007.02.045 PMid:17408854
30. Morimoto, S., Hatsuta, H., Kokubo, Y., Nakano, Y., Hasegawa, M., Yoneda, M., Hirokawa, Y., et al. (2018). Unusual tau pathology of the cerebellum in patients with amyotrophic lateral sclerosis/ parkinsonism-dementia complex from the Kii Peninsula, Japan. Brain Pathol. 28(2): 287-291. https://doi.org/10.1111/bpa.12500 PMid:28236345 PMCid:PMC8028275
31. Volkenhoff, A., Weiler, A., Letzel, M., Stehling, M., Klämbt, C., Schirmeier, S. (2015). Glial glycolysis is essential for neuronal survival in Drosophila. Cell Metab. 22(3): 437-447. https://doi.org/10.1016/j.cmet.2015.07.006 PMid:26235423
32. Castro, T.X., Cubel Garcia, R.D.E., Gonçalves, L.P., Costa, E.M., Marcello, G.C., Labarthe, N.V., Mendes de Almeida, F. (2013). Clinical, hematological, and biochemical findings in puppies with coronavirus and parvovirus enteritis. Can Vet J. 54(9): 885-888.
33. Bhowmik, M., Khanam, R., Vohora, D. (2012). Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: A systemic consideration of recent progress and perspectives. Br J Pharmacol. 167(7): 1398-1414. https://doi.org/10.1111/j.1476-5381.2012.02093.x PMid:22758607 PMCid:PMC3514756
34. Chen, Z., Li, W.D., Zhu, L.J., Shen, Y.J., Wei, E.Q. (2002). Effects of histidine, a precursor of histamine, on pentylenetetrazole-induced seizures in rats. Acta Pharmacol Sin. 23(4): 361-366.
35. Dunn, A.J., Welch, J. (1991). Stress- and endotoxininduced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity. J Neurochem. 57(5): 1615-1622. https://doi.org/10.1111/j.1471-4159.1991.tb06359.x PMid:1717650
36. Spengler, R.N., Allen, R.M., Remick, D.G., Strieter, R.M., Kunkel, S.L. (1990). Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol. 145(5): 1430-1434. https://doi.org/10.4049/jimmunol.145.5.1430 PMid:2166759

Copyright

© 2024 Gülersoy E. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Conflict of Interest Statement

The authors declared that they have no potential lict of interest with respect to the authorship and/or publication of this article.

Citation Information

Macedonian Veterinary Review. Volume 47, Issue 2, Pages 131-140, e-ISSN 1857-7415, p-ISSN 1409-7621, DOI: 10.2478/macvetrev-2024-0024

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