Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-26T06:29:11.809Z Has data issue: false hasContentIssue false
  • English
  • Français

Essential Role of Excessive Tryptophan and its Neurometabolites in Fatigue

Published online by Cambridge University Press:  02 December 2014

Takanobu Yamamoto ,
Hirotsugu Azechi  and
Mary Board
Takanobu Yamamoto*
Affiliation:
Department of Psychology, University Laboratory of Neurophysiology, Tezukayama University, Nara, Japan
Hirotsugu Azechi
Affiliation:
Department of Psychology, University Laboratory of Neurophysiology, Tezukayama University, Nara, Japan
Mary Board
Affiliation:
St. Hilda's College, Cowley Place, Oxford, United Kingdom
*
University Laboratory of Neurophysiology, Department of Psychology, Tezukayama University, 3-1-3 Gakuenminami, Nara 631-8585, Japan.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Purpose:

Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kynurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue.

Materials and Methods:

Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) and to infuse test agents. To examine the kinetics of release, synaptosomes in the striatum were prepared in vitro to measure intra- and extrasynaptosomal concentration of tryptophan, serotonin and 5-HIAA.

Results:

The concentration of tryptophan secreted into the extracellular space of the striatum was higher during fatigue only, and quickly returned to basal levels with recovery from fatigue. Running time to exhaustion was reduced by activation of tryptophan receptors. Time to exhaustion was shorter in NAR, which maintain a higher extracellular level of striatum tryptophan than SDR. Impaired memory performance in a water maze task after tryptophan treatment was attributable to high levels of KYNA and QUIN in the hippocampus acting synergistically on N-methyl-D-aspartic acid receptors. When branched-chain amino acids were administered, tryptophan transport to the extracellular space of the striatum was drastically inhibited.

Conclusion:

Our findings demonstrate that the increase in fatigue which occurs because of excessively elevated brain tryptophan can be further amplified by the use of synthetic KYNA and QUIN.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 39 , Issue 1 , January 2012 , pp. 40 - 47
Copyright
Copyright © The Canadian Journal of Neurological 2012

References

1Greenwood, MH, Lader, MH, Kantameneni, BD, Curzon, G.The acute effects of oral (-)-tryptophan in human subjects. Br J Clin Pharmacol. 1975;2(2):165–72.Google Scholar
2Yamamoto, T, Newsholme, EA.Tryptophan modulates striatal serotonergic activity relative to fatigue. In: Abstracts of the 7th International Congress on Amino Acids and Proteins. Vienna, Austria, August 6-10, 2001. 2001;21(1):55.Google Scholar
3McGuire, J, Ross, GL, Price, H, Mortensen, N, Evans, J, Castell, LM.Biochemical markers for post-operative fatigue after major surgery. Brain Res Bull. 2003;60(1-2):125–30.Google Scholar
4Nemeth, H, Toldi, J, Vécsei, L.Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res. 2005;2(3): 249–60.Google Scholar
5Kurup, RK, Kurup, PA.Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. Int J Neurosci. 2003; 113(5):683–701.Google Scholar
6Prasad, C.Improving mental health through nutrition: the future. Nutrit Neurosci. 2001;4(4):251–72.Google Scholar
7Mackay, GM, Forrest, CM, Stoy, N, et al.Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eur J Neurol. 2006;13(1):30–42.Google Scholar
8Schwarcz, R, Pellicciari, R.Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther. 2002;303(1):1–10.Google Scholar
9Yamamoto, T, Castell, LM, Botella, J, et al.Changes in the albumin binding of tryptophan during postoperative recovery: a possible link with central fatigue? Brain Res Bull. 1997;43(1):43–6.CrossRefGoogle ScholarPubMed
10Gallager, DW, Aghajanian, GK.Inhibition of firing of raphe neurons by tryptophan and 5-hydroxytryptophan: blockade by inhibiting serotonin synthesis with Ro-4-4602. Neuropharm. 1976;15(3): 149–56.CrossRefGoogle ScholarPubMed
11Rassoulpour, A, Wu, HQ, Ferre, S, Schwarcz, R.Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem. 2005;93(3):762–5.CrossRefGoogle ScholarPubMed
12Acworth, I, Nicholass, J, Morgan, B, Newsholme, EA.Effect of sustained exercise on concentrations of plasma aromatic and branched-chain amino acids and brain amines. Biochem Biophys Res Commun. 1986;137(1):149–53.Google Scholar
13Vécsei, L, Beal, MF.Intracerebroventricular injection of kynurenic acid, but not kynurenine, induces ataxia and stereotyped behavior in rats. Brain Res Bull. 1990;25(4):623–7.Google Scholar
14Emori, T, Sugiyama, K, Nagase, S.Tryptophan metabolism in analbuminemic rats. J Biochem. 1983;94(3):623–32.CrossRefGoogle ScholarPubMed
15Yamamoto, T, Newsholme, EA.Diminished central fatigue by inhibition of the L-system transporter for the uptake of tryptophan. Brain Res Bull. 2000;52(1):35–8.Google Scholar
16Central, Fatigue, Chapter 9, Metabolism in Exercise. In: Newsholme, EA, Leech, A, editors. Biochemistry for the Medical Sciences. Chichester: Wiley; 1983. p 366–77.Google Scholar
17Morris, R.Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11(1): 47–60.Google Scholar
18Sidransky, H, Verney, E, Kurl, R.Comparison of effects of Ltryptophan and a tryptophan analog, D, L-beta-(1-Naphthyl) alanine, on processes relating to hepatic protein synthesis in rats. J Nutr. 1990;120(10):1157–62.Google Scholar
19Yamamoto, T, Newsholme, EA.The effect of tryptophan deficiency in the brain on rat fatigue levels: a rat model of fatigue reduction. Adv Exp Med Biol. 2003;527:527–30.Google Scholar
20Höckel, SHJ, Müller, WE, Wollert, U.Regional distribution of high-affinity L-tryptophan uptake in rat brain. Neurosci Lett. 1978;8 (1):65–9.Google Scholar
21Martinet, M, Fonlupt, P, Pacheco, H.Kinetics of tryptophan accumulation into synaptosomes of various regions of rat brain. Psychopharmacol. 1979;66(1):63–6.Google Scholar
22Yamamoto, T, Newsholme, EA.Central fatigue, exercise and behaviour. Taiikuno kagaku (Journal of Health, Physical Education and Recreation). 2002;52:198–202 (in Japanese).Google Scholar
23Forrest, CM, Mackay, GM, Stoy, N, et al.Tryptophan loading induces oxidative stress. Free Rad Res. 2004;38(11):1167–71.CrossRefGoogle ScholarPubMed
24Hilmas, C, Pereira, EF, Alkondon, M, Rassoulpour, A, Schwarcz, R, Albuquerque, EX.The brain metabolite kynurenic acid inhibits α7 nicotinic receptor expression: Physiopathological implications. J Neurosci. 2001;21(19):7463–73.CrossRefGoogle ScholarPubMed