Reduced Glutamatergic Neurotransmission as Possible Indicator of Unfavorable Prognosis

Elena V. Alekseeva, PhD

Central Clinical Hospital of the Presidential Administration of the Russian Federation; Moscow, the Russian Federation

*Corresponding author: Elena V. Alekseeva, PhD, anesthesiologist-resuscitator of the intensive care unit; the Central Clinical Hospital of the Presidential Administration of the Russian Federation. Moscow, the Russian Federation. E-mail: aev_69@mail.ru.

Published: March 17, 2017.  doi: 10.21103/Article7(1)_RA2

Abstract: 

The paper summarizes the results of experimental and clinical studies showing a reduced function of the glutamatergic neurotransmitter system (GNS) in the development of critical states of the organism. Reduced function of GNS is considered as an unfavorable prognostic factor associated with key mechanisms of thanatogenesis.

Keywords: 
glutamate ● glutamine ● kynurenic acid ● critically ill patients
References: 

1. Jobard E, Trédan O, Postoly D, André F, Martin AL, Elena-Herrmann B, et al. A Systematic Evaluation of Blood Serum and Plasma Pre-Analytics for Metabolomics Cohort Studies. Int J Mol Sci. 2016; 17(12). pii: E2035.
2. Antcliffe D, Gordon AC. Metabonomics and intensive care. Crit Care. 2016; 20:68. doi: 10.1186/s13054-016-1222-8.
3. Beger RD, Dunn W, Schmidt MA, Gross SS, Kirwan JA, Cascante M, et al. Metabolomics enables precision medicine: "A White Paper, Community Perspective".Metabolomics. 2016; 12(10):149.
4. Mazzoli R, Pessione E. The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling. Front Microbiol. 2016; 7:1934.
5. Hinoi E, Takarada T, Ueshima T, Tsuchihashi Y, Yoneda Y. Hinoi, E. Glutamate signaling in peripheral tissues. Eur J Biochem.2004; 271(1):1-13.
6. Perfilova VN, Tyurenkov IN. Glutamate lonotropic Receptors: Structure, Localisation, Function. Usp Fiziol Nauk. 2016;47(1):80-96. [Article in Russian].
7. Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, et al. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J. 2007; 406(3):407-14.
8. Tremolizzo L, Sala G, Zoia CP, Ferrarese C. Assessing Glutamatergic Function and Dysfunction in Peripheral Tissues. Current Medicinal Chemistry. 2012; 19(9):1310-5.
9. Filpa V, Moro E, Protasoni M, Crema F, Frigo G, Giaroni C. Role of glutamatergic neurotransmission in the enteric nervous system and brain-gut axis in health and disease. Neuropharmacology. 2016;111:14-33. doi: 10.1016/j.neuropharm.2016.08.024.
10. Abramov Yu B. Immune aspects of the central mechanisms of pain. Bol’. 2009; 4:2-8. [Article in Russian].
11.  Davydova ON, Boldyrev AA. Glutamate receptors in cells of the nervous and immune systems. Annaly Klinicheskoy i Eksperimental’noy Nevrologiiю 2007;4:28-34. [Article in Russian].
12. Stojic I, Srejovic I, Zivkovic V, Jeremic N, Djuric M, Stevanovic A, et al. The effects of verapamil and its combinations with glutamate and glycine on cardiodynamics, coronary flow and oxidative stress in isolated rat heart J Physiol Biochem. 2016; Nov 3. [Epub ahead of print]
13. Fujita S, Yokoyama U, Ishiwata R, Aoki R, Nagao K, Masukawa D, et al. Glutamate Promotes Contraction of the Rat Ductus Arteriosus. Circ J. 2016;80(11):2388-2396.
14. Ishibashi-Shiraishi I, Shiraishi S, Fujita S, Ogawa S, Kaneko M, Suzuki M, et al. L-Arginine L-Glutamate Enhances Gastric Motor Function in Rats and Dogs and Improves Delayed Gastric Emptying in Dogs.J Pharmacol Exp Ther. 2016;359(2):238-246.
15. Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LE. Glutamate in dopamine neurons: synaptic versus diffuse transmission. Brain Res Rev. 2008; 58(2):290-302.
16. Hnasko TS, Edwards RH. Neurotransmitter corelease: mechanism and physiological role. Annu Rev Physiol. 2012; 74:225-43. doi: 10.1146/annurev-physiol-020911-153315.
17.  Uchida N. Bilingual neurons release glutamate and GABA. Nat Neurosci. 2014;17(11):1432-4. doi: 10.1038/nn.3840.
18. Gomazkov OA. Neurogenesis as the adaptive function of the brain. Institute of Biomedical Chemistry named after V.N. Orekhovich: Moscow; 2014.
19. Brodsky VY, Malchenko LA, Konchenko DS, Zvezdina ND, Dubovaya TK. Glutamic Acid - Amino Acid, Neurotransmitter, and Drug - Is Responsible for Protein Synthesis Rhythm in Hepatocyte Populations in vitro and in vivo. Biochemistry (Mosc). 2016;81(8):892-8. DOI: 10.1134 / S0006297916080101.
20.  Du J, Li X.H, Li YJ. Glutamate in peripheral organs: biology and pharmacology. Eur J Pharmacol. 2016;784:42-8. doi: 10.1016/j.ejphar.2016.05.009.
21. Aleksandrova EV, Zaytsev OS, Potapov AA. Clinical syndromes of neurotransmitter system dysfunction in severe brain injury. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2015;115(7):40-6. [Article in Russian].
22.Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30(4):379-87. doi: 10.1038/aps.2009.
23. Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157-88. doi: 10.1016/j.pneurobio.2013.11.006.
24. Chen X, Wang K. The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995-2015. Acta Pharm Sin B. 2016; 6 (6):522-30.
25. Castillo J, Loza MI, Mirelman D, Brea J, Blanco M, Sobrino T et al. A novel mechanism of neuroprotection: Blood glutamate grabber. J Cereb Blood Flow Metab. 2016;36(2):292-301. doi: 10.1177/0271678X15606721.
26. Gan'shina TS, Kurza EV, Kurdyumov IN, Maslennikov DV, Mirzoyan RS. Peculiarities of the cerebrovascular effects of glutamic acid. Eksp Klin Farmakol. 2016;79(3):9-12.
27. Ryabov GA. Hypoxia in critical states. M.: Meditsina; 1988.
28.   Timofeev IV. Illness and death. Selected lectures on clinical pathology and thanatology. St. Petersburg: DNA; 2016.
29. Wolahan SM, Hirt D, Glenn TC. Translational Metabolomics of Head Injury: Exploring Dysfunctional Cerebral Metabolism with Ex Vivo NMR Spectroscopy-Based Metabolite Quantification. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 25.
30. Pozdeev VK. The neurochemical methods in clinical practice. St. Petersburg: Renome; 2013.
31. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr. 2003;133(6 Suppl 1):2068S-2072S.
32. Bein BN, Yezhova AA. Changes in the spectrum of free amino acids in the blood serum of patients with cerebrovascular disease. Vyatskii Med Vestnik. 2007; 2-3:5-7. [Article in Russian].
33. Leibowitz A, Klin Y, Gruenbaum BF, Gruenbaum SE, Kuts R, Dubilet M et al. Effects of strong physical exercise on blood glutamate and its metabolite 2-ketoglutarate levels in healthy volunteers. Acta Neurobiol Exp (Wars). 2012; 72(4):385-96.
34. Sem’yanov AV, Kazantsev VB. Neuron-glia interactions in the brain. Nizhny Novgorod; 2007.
35. Albuquerque EX, Schwarcz R. Kynurenic acid as an antagonist of α7 nicotinic acetylcholine receptors in the brain: facts and challenges. Biochem Pharmacol. 2013; 85(8): 1027–32. doi: 10.1016/j.bcp.2012.12.014.
36. Tuboly G, Tar L, Bohar Z, Safrany-Fark A, Petrovszki Z, Kekesi G et al. The inimitable Kinurenic acid: the roles of different ionotropic receptors in the action of Kinurenic acid at a spinal level. Brain Res Bull. 2015;112:52-60. doi: 10.1016/j.brainresbull.2015.02.001.
37. Wang Y, Moquin KF, Michael AC. Evidence for coupling between steady-state and dynamic extracellular dopamine concentrations in the rat striatum. J Neurochem. 2010 114(1):150-9. doi: 10.1111/j.1471-4159.2010.06740.
38. Passera E, Campanini B, Rossi F, Casazza V, Rizzi M, Pellicciari R et al. Human Kinurenine aminotransferase II--reactivity with substrates and inhibitors. FEBS J. 2011 ;278(11):1882-900. doi: 10.1111/j.1742-4658.2011.08106.
39. Borland LM, Michael AC. Voltammetric study of the control of striatal dopamine release by glutamat. J Neurochem. 2004; 91 (1): 220-9.
40. Chen DY, Chen YM, Chien HJ, Lin CC, Hsieh CW, Chen HH et al. Metabolic Disturbances in Adult-Onset Still's Disease Evaluated Using Liquid Chromatography/Mass Spectrometry-Based Metabolomic Analysis. PLoS One. 2016; 11(12):e0168147. doi: 10.1371/journal.pone.0168147.
41. Theodoridis G, Gika HG, Wilson ID. LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics. TRAC Trends Analytical Chem 2008; 27:251–260.
42. Dias DA, Jones OA, Beale DJ, Boughton BA, Benheim D, Kouremenos KA et al. Current and Future Perspectives on the Structural Identification of Small Molecules in Biological Systems. Metabolites. 2016; 6(4). pii: E46.
43. Godlewska BR, Pike A, Sharpley AL, Ayton A, Park RJ, Cowen PJ et al. Brain glutamate in anorexia nervosa: a magnetic resonance spectroscopy case control study at 7 Tesla.  Psychopharmacology (Berl). 2017;234(3):421-426. doi: 10.1007/s00213-016-4477-5.
44. Kwon YK, Ha IJ, Bae HW, Jang WG, Yun HJ, Kim SR et al. Dose-dependent metabolic alterations in human cells exposed to gamma irradiation. PLoS One.2014; 9 (11) – e113573. doi: 10.1371/journal.pone.0113573.
45. Korochanskaya SP, Storozhuk PG, Bykov IM.  Educational and methodical manual on biological chemistry. Krasnodar; 2016.
46. Poeze M, Luiking YC, Breedveld P, Manders S, Deutz NE. Decreased plasma glutamate in early phases of septic shock with acute liver dysfunction is an independent predictor of survival. Clin Nutr. 2008;27(4):523–30. doi: 10.1016/j.clnu.2008.04.006.
47. Hirose T, Shimizu K, Ogura H, Tasaki O, Hamasaki T, Yamano S et al. Altered balance of the aminogram in patients with sepsis – The relation to mortality. Clin Nutr. 2014; 33(1):179-82. doi: 10.1016/j.clnu.2013.11.017. 
48. Alekseeva EV, Popova TS, Sal’nikov PS. Low levels of glutamine, glutamic acid and citrulline in plasma as risk factors for the 28-day survival in critically ill patients. Patogenez. 2016; 14 (2): 48-57. [Article in Russian].
49.  Alekseeva EV. Possibility of correction of hypofunction of glutamatergic neurotransmitter system in critically ill patients. Kremlin medicine. Clin Vestnik. 2016; 4: 137-151. [Article in Russian].
50. Buter H, Koopmans M, Kemperman R, Jekel L, Boerma C. Plasma glutamine levels before cardiac surgery are related to post-surgery infections; an observational study. J Cardiothorac Surg. 2016;11(1):155.
51. Lin YR, Li CJ, Syu SH, Wen CH, Buddhakosai W, Wu HP et al. Early Administration of Glutamine Protects Cardiomyocytes from Post-Cardiac Arrest Acidosis. Biomed Res Int. 2016; 2016:2106342. doi: 10,1155 / 2016/2106342.
52. Dabrowski W, Kocki T, Pilat J, Parada-Turska J, Malbrain ML. Changes in plasma kynurenic acid concentration in septic shock patients undergoing continuous veno-venous haemofiltration. Inflammation. 2014;37(1):223-34. doi: 10.1007/s10753-013-9733-9.
53. Ristagno G, Latini R, Vaahersalo J, Masson S, Kurola J, Varpula T et al. Early activation of the kynurenine pathway predicts early death and long-term outcome in patients resuscitated from out-of-hospital cardiac arrest. J Am Heart Assoc. 2014; 3(4). pii: e001094. doi: 10.1161/JAHA.114.001094.
54. Darlington LG, Mackay GM, Forrest CM, Stoy N, George C, Stone TW. Altered kynurenine metabolism correlates with infarct volume in stroke. Eur J Neurosci. 2007; 26(8):2211-21.
55. Alekseeva EV. Changes in plasma content of glutamic acid in critically ill patients during hypoxia. Journal of Modern Clinical Medicine. 2016;9(5):14-25.[Article in Russian].
56. Brose SA, Marquardt AL, Golovko MY. Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia J Neurochem. 2014; 129(3):400-12. doi: 10.1111/jnc.12617.
57. Fan J, Kamphorst JJ, Rabinowitz JD, Shlomi T. Fatty acid labeling from glutamine in hypoxia can be explained by isotope exchange without net reductive isocitrate dehydrogenase (IDH) flux. J Biol Chem. 2013; 288 (43):31363–9. doi: 10.1074/jbc.M113.502740.
58. Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol. 2013; 9:712. doi: 10.1038/msb.2013.65.
59. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature.2011; 481 (7381): 380–4. doi: 10.1038/nature10602.
60. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. 2011;108(49):19611–6. doi: 10.1073/pnas.1117773108.
61. Baran H, Kepplinger B, Herrera-Marschitz M, Stolze K, Lubec G, Nohl H. Increased kynurenic acid in the brain after neonatal asphyxia. Life Sci. 2001; 69(11): 1249-56.
62. Ashmarin IP,  Stukalov VP. Neurochemistry. Institute of Biomedical Chemistry of the RAMS: Moscow; 1996.
63. Ceresoli-Borroni G, Schwarcz R. Neonatal asphyxia in rats: acute effects on cerebral kynurenine metabolism. Pediatr. Res. 2001;50:231–5.
64. Chua HR, Baldwin I, Fealy N, Naka T, Bellomo R. Amino acid balance with extended daily diafiltration in acute kidney injury. Blood Purif. 2012 ;33(4):292-9. doi: 10.1159/000335607.
65. Alekseeva EV, Sal’nikov PS. Changes in the levels of glutamic acid and glutamate in  the blood plasma of the critically ill patients with impaired liver and kidney function. Pathogenez. 2016; 14(1):72-83. [Article in Russian].
66. Duran MA, Spencer D, Weise M, Kronfol NO, Spencer RF, Oken DE. Renal epithelial amino acid concentrations in mercury-induced and postischemic acute renal failure. Toxicol Appl Pharmacol. 1990; 105(2):183–94.
67. Goldstein RE, Marks SL, Cowgill LD, Kass PH, Rogers QR. Plasma amino acid profiles in cats with naturally acquired chronic renal failure. Am J Vet Res.1999; 60(1):109–13.
68. Montañés I, Badía A, Réngel MA, López-Novoa J M. Renal cortical intermediary metabolism in the recovery phase of postischemic acute renal failure in the dog. Proc Soc Exp Biol Med. 1992;199(3):321–6.
69. Sallée M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins (Basel). 2014; 6(3):934-49. doi: 10.3390/toxins6030934.
70. Terent’yev AA, Kazimirsky AN, Efremov AD. Biological oxidation and bio-energy. N.I. Pirogov RNRMU Moscow; 2012.
71. Pawlak D, Pawlak K, Malyszko J, Mysliwiec M, Buczko W. Accumulation of toxic products degradation of kynurenine in hemodialyzed patients. Int Urol Nephrol. 2001;33(2):399-404.
72.Pawlak D, Tankiewicz A, Buczko W. Kynurenine and its metabolites in the rat with experimental renal insufficiency. J Physiol Pharmacol. 2001;52(4 Pt 2):755-66.
73. Langley RJ, Tsalik EL, van Velkinburgh JC, Glickman SW, Rice BJ, Wang C et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013;5(195):195ra95. doi: 10.1126/scitranslmed.3005893.
74. Mickiewicz B, Tam P, Jenne CN, Leger C, Wong J, Winston BW. Alberta Sepsis Network. Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit. Crit Care. 2015; 19:11. doi: 10.1186/s13054-014-0729-0.
75.  Alekseeva EV. Selected aspects of the necessity in the correction of the decreased   glutamic acid content in patients with severe sepsis and septic shock. Vestnik Sovremennoi Klinicheskoi Medicinye. 2016;6:169-78.[Article in Russian].
76. Boutry C, Matsumoto H, Bos C, Moinard C, Cynober L, Yin Y. Decreased glutamate, glutamine and citrulline concentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine supplementation: a primary intestinal defect ? Amino Acids. 2012;43(4):1485–98.
77. Noworyta-Sokołowska K, Górska A, Gołembiowska K. LPS-induced oxidative stress and inflammatory reaction in the rat striatum. Pharmacol Rep. 2013;65(4):863–9.
78. Sabadash EV, Skornyakov SN. The method for assessing the severity of TB infection. RF Patent № 2305286. UNIIF State Agency for Health Care; appl. 22.08.2005; publ. 27.08.2007. 79. Buter H, Bakker AJ, Kingma WP, Koopmans M, Boerma EC. Plasma glutamine levels in patients after non-elective or elective ICU admission: an observational study. BMC Anesthesiol. 2016;16:15. doi: 10.1186/s12871-016-0180-7.
80. Kotlinska-Hasiec E, Nowicka-Stazka P, Parada-Turska J, Stazka K, Stazka J, Zadora P et al. Plasma kynurenic acid concentration in patients undergoing cardiac surgery: effect of anaesthesia. Arch Immunol Ther Exp (Warsz). 2015;63(2):129–37. doi: 10.1007/s00005-014-0312-z.
81. Turski MP, Turska M, Paluszkiewicz P, Parada-Turska J, Oxenkrug GF.  Kynurenic acid in the digestive system: new facts, new challenges. Int J Tryptophan Res. 2013; 6:47–55.
82. Mándi Y, Vécsei L. The Kinurenine system and immunoregulation. J Neural. Transm. 2012;119(2):197-209. doi: 10.1007/s00702-011-0681-y.
83. Schmidt SV, Schultze JL. New Insights into IDO Biology in Bacterial and Viral Infections. Front Immunol. 2014;5:384. doi: 10.3389/fimmu.2014.00384.
84. Tattevin P, Monnier D, Tribut O, Dulong J, Bescher N, Mourcin F, et al. Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J Infect Dis. 2010; 201(6): 956-66. doi: 10.1086/650996.
85. Schefold JC, Zeden JP, Fotopoulou C, von Haehling S, Pschowski R, Hasper D, et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant. 2009;24:1901–8. doi: 10.1093/ndt/gfn739.
86. Zeden JP, Fusch G, Holtfreter B, Schefold JC, Reinke P, Domanska G, et al. Excessive tryptophan catabolism along the kynurenine pathway precedes ongoing sepsis in critically ill patients. Anaesth Intensive Care.2010; 38:307–16.
87. Soeters PB, Grecu I. Have we enough glutamine and how does it work? A clinician's view. Ann. Nutr. Metab. 2012;60(1):17–26. doi: 10.1159/000334880.
88. Shilov YE, Bezrukov MV. Kynurenines in pathogenesis of endogenous psychiatric disorders. Annals of the Russian academy of medical sciences. 2013;68(1):35-41.doi:10.15690/vramn.v68i1.535 [Article in Russian].
89. Chiappelli J, Pocivavsek A, Nugent KL, Notarangelo FM, Kochunov P, Rowland LM et al. Stress-induced increase in Kinurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance. JAMA Psychiatry.2014;71(7):761-8. doi: 10.1001/jamapsychiatry.2014.243.
90. Kotlinska-Hasiec E, Nowicka-Stazka P, Parada-Turska J, Stazka K, Stazka J, Zadora P et al. Plasma Kinurenic acid concentration in patients undergoing cardiac surgery: effect of anaesthesia. Arch Immunol Ther Exp (Warsz). 2015; 63(2):129-37. doi: 10.1007/s00005-014-0312-z.
91. Wernerman J. How to understand the results of studies of glutamine supplementation. Crit Care. 2015;19:385. doi: 10.1186/s13054-015-1090-7.
92. Wernerman J. What Is Actually Attributable to Glutamine? JPEN J Parenter Enteral Nutr. 2017;41(1):9. doi: 10,1177 / 0148607116637938.

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