Generic placeholder image

Current Pharmaceutical Analysis


ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

Research Article

Simultaneous Determination of D-amino Acids in Rat Urine by Highperformance Liquid Chromatography-tandem Mass Spectrometry Method: Application to Investigate the Clinical Value of D-amino Acids in the Early Diagnosis of Alzheimer’s Disease

Author(s): Min Zhang, Shuting Zhang, Weichao Yu, Xiaoyan Li, Ning Ma and Yan Cui*

Volume 17, Issue 8, 2021

Published on: 17 July, 2020

Page: [1026 - 1035] Pages: 10

DOI: 10.2174/1573412916999200717235048

Price: $65


Background: D-amino acids are closely related to the development and progression of Alzheimer's disease (AD) and are expected as the novel biomarkers for AD diagnosis.

Objective: The aim was to investigate the potential clinical value of D-amino acids for Alzheimer's disease.

Methods: A simple and sensitive HPLC/MS-MS method was developed for the simultaneous determination of D-alanine, D-glutamine, D-proline and D-serine in rat urine. The samples were firstly pretreated by methanol, then derivatized by 7-chloro-4-nitrobenzoxadiazole with Fudosteine as internal standard, enantioseparated on Sumichiral OA-2500S column, using a mobile phase composed of acetonitrile- methanol (50:50, v/v) containing 0.5% formic acid, and detected with 4000 Qtrap MS/MS in electrospray-ionization source by negative ion mode.

Results: The established method was successfully applied to determine the D-amino acid levels in rat urine from 20 Alzheimer's disease rats and 20 age-matched normal controls. The mean levels of Damino acids in the urine of Alzheimer's disease rats were all significantly lower than those in normal controls. Based on the contents of D-amino acids, the distinction model between Alzheimer's disease rats and normal controls was established by the Bayesian discriminant analysis.

Conclusion: The relationship between Alzheimer's disease and D-amino acids revealed that D-amino acids would be potential biomarkers for Alzheimer’s disease.

Keywords: D-amino acids, Alzheimer's disease, biomarkers, HPLC/MS-MS, simultaneous determination, enantioseparation.

Graphical Abstract
Zhang, X.Z.; Quan, Y.; Tang, G.Y. Medical genetics-based drug repurposing for Alzheimer’s disease. Brain Res. Bull., 2015, 110, 26-29.
[] [PMID: 25446738]
Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C.P. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement., 2013. 9, 63-75. e2.
Dubois, B.; Feldman, H.H.; Jacova, C.; Cummings, J.L.; Dekosky, S.T.; Barberger-Gateau, P.; Delacourte, A.; Frisoni, G.; Fox, N.C.; Galasko, D.; Gauthier, S.; Hampel, H.; Jicha, G.A.; Meguro, K.; O’Brien, J.; Pasquier, F.; Robert, P.; Rossor, M.; Salloway, S.; Sarazin, M.; de Souza, L.C.; Stern, Y.; Visser, P.J.; Scheltens, P. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol., 2010, 9(11), 1118-1127.
[] [PMID: 20934914]
Sperling, R.A.; Aisen, P.S.; Beckett, L.A.; Bennett, D.A.; Craft, S.; Fagan, A.M.; Iwatsubo, T.; Jack, C.R., Jr; Kaye, J.; Montine, T.J.; Park, D.C.; Reiman, E.M.; Rowe, C.C.; Siemers, E.; Stern, Y.; Yaffe, K.; Carrillo, M.C.; Thies, B.; Morrison-Bogorad, M.; Wagster, M.V.; Phelps, C.H. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 280-292.
[] [PMID: 21514248]
Visser, P.J.; Vos, S.; van Rossum, I.; Scheltens, P. Comparison of International Working Group criteria and National Institute on Aging-Alzheimer’s Association criteria for Alzheimer’s disease. Alzheimers Dement., 2012, 8(6), 560-563.
[] [PMID: 23102126]
Robinson, R.A.; Amin, B.; Guest, P.C. Multiplexing biomarker methods, proteomics and considerations for alzheimer’s disease. Adv. Exp. Med. Biol., 2017, 974, 21-48.
[] [PMID: 28353223]
Blennow, K.; Hampel, H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol., 2003, 2(10), 605-613.
[] [PMID: 14505582]
McKhann, G.M.; Knopman, D.S.; Chertkow, H.; Hyman, B.T.; Jack, C.R., Jr; Kawas, C.H.; Klunk, W.E.; Koroshetz, W.J.; Manly, J.J.; Mayeux, R.; Mohs, R.C.; Morris, J.C.; Rossor, M.N.; Scheltens, P.; Carrillo, M.C.; Thies, B.; Weintraub, S.; Phelps, C.H. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 263-269.
[] [PMID: 21514250]
Dubois, B.; Feldman, H.H.; Jacova, C.; Dekosky, S.T.; Barberger-Gateau, P.; Cummings, J.; Delacourte, A.; Galasko, D.; Gauthier, S.; Jicha, G.; Meguro, K.; O’brien, J.; Pasquier, F.; Robert, P.; Rossor, M.; Salloway, S.; Stern, Y.; Visser, P.J.; Scheltens, P. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol., 2007, 6(8), 734-746.
[] [PMID: 17616482]
Visser, P.J.; Verhey, F.; Knol, D.L.; Scheltens, P.; Wahlund, L.O.; Freund-Levi, Y.; Tsolaki, M.; Minthon, L.; Wallin, A.K.; Hampel, H.; Bürger, K.; Pirttila, T.; Soininen, H.; Rikkert, M.O.; Verbeek, M.M.; Spiru, L.; Blennow, K. Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol., 2009, 8(7), 619-627.
[] [PMID: 19523877]
Mulder, C.; Verwey, N.A.; van der Flier, W.M.; Bouwman, F.H.; Kok, A.; van Elk, E.J.; Scheltens, P.; Blankenstein, M.A. Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin. Chem., 2010, 56(2), 248-253.
[] [PMID: 19833838]
Corrigan, J.J. D-amino acids in animals. Science, 1969, 164(3876), 142-149.
[] [PMID: 5774186]
Müller, C.; Fonseca, J.R.; Rock, T.M.; Krauss-Etschmann, S.; Schmitt-Kopplin, P. Enantioseparation and selective detection of D-amino acids by ultra-high-performance liquid chromatography/mass spectrometry in analysis of complex biological samples. J. Chromatogr. A, 2014, 1324, 109-114.
[] [PMID: 24315356]
Miyoshi, Y.; Koga, R.; Oyama, T.; Han, H.; Ueno, K.; Masuyama, K.; Itoh, Y.; Hamase, K. HPLC analysis of naturally occurring free D-amino acids in mammals. J. Pharm. Biomed. Anal., 2012, 69, 42-49.
[] [PMID: 22386210]
Chervyakov, A.V.; Gulyaeva, N.V.; Zakharova, M.N. D-amino acids in normal ageing and pathogenesis of neurodegenerative diseases. Neurochem. J., 2011, 5, 100-114.
Nishikawa, T. Analysis of free d-serine in mammals and its biological relevance. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2011, 879, 0-3183.
Li, X.Y.; Cui, Y.; Xing, Y.P.; Lv, C.H.X.; Li, Q.; Bi, K.S.H. Simultaneous quantitation of nine kinds of (d)- and (l)-amino acid enantiomers by HPLC-MS/MS: application to the quality control of amino acid tablets. Anal. Methods, 2015, 7, 8817-8825.
Li, Z.; Xing, Y.; Guo, X.; Cui, Y. Development of an UPLC-MS/MS method for simultaneous quantitation of 11 d-amino acids in different regions of rat brain: Application to a study on the associations of d-amino acid concentration changes and Alzheimer’s disease. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2017, 1058, 40-46.
[] [PMID: 28531844]
Romano, D.; Molla, G.; Pollegioni, L.; Marinelli, F. Optimization of human D-amino acid oxidase expression in Escherichia coli. Protein Expr. Purif., 2009, 68(1), 72-78.
[] [PMID: 19497370]
Madeira, C.; Lourenco, M.V.; Vargas-Lopes, C.; Suemoto, C.K.; Brandão, C.O.; Reis, T.; Leite, R.E.; Laks, J.; Jacob-Filho, W.; Pasqualucci, C.A.; Grinberg, L.T.; Ferreira, S.T.; Panizzutti, R. d-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl. Psychiatry, 2015, 5e561
[] [PMID: 25942042]
Yamazaki, D.; Horiuchi, J.; Ueno, K.; Ueno, T.; Saeki, S.; Matsuno, M.; Naganos, S.; Miyashita, T.; Hirano, Y.; Nishikawa, H.; Taoka, M.; Yamauchi, Y.; Isobe, T.; Honda, Y.; Kodama, T.; Masuda, T.; Saitoe, M. Glial dysfunction causes age-related memory impairment in Drosophila. Neuron, 2014, 84(4), 753-763.
[] [PMID: 25447741]
Hamase, K.; Takagi, S.; Morikawa, A.; Konno, R.; Niwa, A.; Zaitsu, K. Presence and origin of large amounts of D-proline in the urine of mutant mice lacking D-amino acid oxidase activity. Anal. Bioanal. Chem., 2006, 386(3), 705-711.
[] [PMID: 16924383]
Xing, Y.; Li, X.; Guo, X.; Cui, Y. Simultaneous determination of 18 D-amino acids in rat plasma by an ultrahigh-performance liquid chromatography-tandem mass spectrometry method: application to explore the potential relationship between Alzheimer’s disease and D-amino acid level alterations. Anal. Bioanal. Chem., 2016, 408(1), 141-150.
[] [PMID: 26497841]
Barañano, D.E.; Ferris, C.D.; Snyder, S.H. Atypical neural messengers. Trends Neurosci., 2001, 24(2), 99-106.
[] [PMID: 11164940]
Zhao, S.; Liu, Y.M. Electrophoretic separation of tryptophan enantiomers in biological samples. Electrophoresis, 2001, 22(13), 2769-2774.
[<2769:AID-ELPS2769>3.0.CO;2-H] [PMID: 11545406]
Kato, S.; Kito, Y.; Hemmi, H.; Yoshimura, T. Simultaneous determination of d-amino acids by the coupling method of d-amino acid oxidase with high-performance liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2011, 879, 0-3195.
Szökő, É.; Vincze, I.; Tábi, T. Chiral separations for d-amino acid analysis in biological samples. J. Pharm. Biomed. Anal., 2016, 130, 100-109.
[] [PMID: 27435607]
Ilisz, I.; Aranyi, A.; Péter, A. Chiral derivatizations applied for the separation of unusual amino acid enantiomers by liquid chromatography and related techniques. J. Chromatogr. A, 2013, 1296, 119-139.
[] [PMID: 23598164]
Sarma, S.N.; Saleem, A.; Lee, J.Y.; Tokumoto, M.; Hwang, G.W.; Man Chan, H.; Satoh, M. Effects of long-term cadmium exposure on urinary metabolite profiles in mice. J. Toxicol. Sci., 2018, 43(2), 89-100.
[] [PMID: 29479038]
Giuliani, D.; Mioni, C.; Altavilla, D.; Leone, S.; Bazzani, C.; Minutoli, L.; Bitto, A.; Cainazzo, M.M.; Marini, H.; Zaffe, D.; Botticelli, A.R.; Pizzala, R.; Savio, M.; Necchi, D.; Schiöth, H.B.; Bertolini, A.; Squadrito, F.; Guarini, S. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology, 2006, 147(3), 1126-1135.
[] [PMID: 16254026]
Giuliani, D.; Zaffe, D.; Ottani, A.; Spaccapelo, L.; Galantucci, M.; Minutoli, L.; Bitto, A.; Irrera, N.; Contri, M.; Altavilla, D.; Botticelli, A.R.; Squadrito, F.; Guarini, S. Treatment of cerebral ischemia with melanocortins acting at MC4 receptors induces marked neurogenesis and long-lasting functional recovery. Acta Neuropathol., 2011, 122(4), 443-453.
[] [PMID: 21927944]
Katane, M.; Homma, H. D-aspartate oxidase: the sole catabolic enzyme acting on free D-aspartate in mammals. Chem. Biodivers., 2010, 7(6), 1435-1449.
[] [PMID: 20564562]
Mothet, J.P.; Pollegioni, L.; Ouanounou, G.; Martineau, M.; Fossier, P.; Baux, G. Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc. Natl. Acad. Sci. USA, 2005, 102(15), 5606-5611.
[] [PMID: 15800046]
Panatier, A.; Theodosis, D.T.; Mothet, J.P.; Touquet, B.; Pollegioni, L.; Poulain, D. A.; Oliet, H. Glia-derived d-serine controls nmda receptor activity and synaptic memory. Cell., 2006, 125, 0-784.
Mothet, J.P.; Rouaud, E.; Sinet, P.M.; Potier, B.; Jouvenceau, A.; Dutar, P.; Videau, C.; Epelbaum, J.; Billard, J.M. A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory. Aging Cell, 2006, 5(3), 267-274.
[] [PMID: 16842499]
Wu, G.M.; Hou, X.Y. Oligomerized Abeta25-35 induces increased tyrosine phosphorylation of NMDA receptor subunit 2A in rat hippocampal CA1 subfield. Brain Res., 2010, 1343, 186-193.
[] [PMID: 20441772]
Wolosker, H.; Dumin, E.; Balan, L.; Foltyn, V.N. D-amino acids in the brain: D-serine in neurotransmission and neurodegeneration. FEBS J., 2008, 275(14), 3514-3526.
[] [PMID: 18564180]
Di Maria, E.; Bonvicini, C.; Bonomini, C.; Alberici, A.; Zanetti, O.; Gennarelli, M. Genetic variation in the G720/G30 gene locus (DAOA) influences the occurrence of psychotic symptoms in patients with Alzheimer’s disease. J. Alzheimers Dis., 2009, 18(4), 953-960.
[] [PMID: 20009237]
Ohide, H.; Miyoshi, Y.; Maruyama, R.; Hamase, K.; Konno, R. D-Amino acid metabolism in mammals: biosynthesis, degradation and analytical aspects of the metabolic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2011, 879(29), 3162-3168.
[] [PMID: 21757409]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy