Diminished central fatigue by inhibition of the L-system transporter for the uptake of tryptophan

doi:10.1016/S0361-9230(99)00276-2

Brain Research Bulletin

Volume 52, Issue 1, 1 May 2000, Pages 35-38

https://doi.org/10.1016/S0361-9230(99)00276-2 Get rights and content

Abstract

Nagase genetically analbuminemic rats (NAR) were run to fatigue. Administration of branched chain amino acids (BCAA) before exhaustive exercise, resulted in a post-fatigue decreased tryptophan uptake (−22%, p < 0.05) and 5-hydroxytryptophan (5-HTP) uptake (−29%, p < 0.01) into the synaptosomes isolated from the striatum when compared with saline administration. At the same time, NAR who received either BCAA or 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH, a specific inhibitor for the L-system transporter) had a considerably prolonged run time to exhaustion (by twofold), compared to those who received either saline or albumin treatments. When classified by run time, it was of interest that, when the data for BCAA and BCH treatments for the longer run time NAR (Group B) was combined, it gave rise to a significant decrease in synaptosomal tryptophan and 5-HTP of a similar magnitude to that observed with BCAA alone. These levels were lower than those observed in NAR in the shorter run time group (Group A) for all treatments.

These results support the view that an activated serotonergic function may be involved in central fatigue, which can be diminished by inhibition of the L-system transporter.

Introduction

Tryptophan and branched chain amino acids (BCAA) are transported into the brain by the L-system transporter of the blood—brain barrier [15]. Plasma tryptophan is unique among amino acids in that it binds to albumin in the blood. Free tryptophan competes with BCAA for entry across the L-system transporter into the blood—brain barrier. It has been reported that, during post-operative recovery in patients, there is an increased ratio of plasma free tryptophan for the BCAA [19]. An enhanced plasma concentration ratio of tryptophan/BCAA has also been observed in animals with fatigue after exercise [2]. Thus it was postulated that a high plasma concentration ratio of free tryptophan/BCAA might result in an increased tryptophan uptake into the tissues of the six different brain regions [2] and into striatal synaptosomes [19]. Since tryptophan is the precursor for 5-hydroxytryptamine (5-HT), this could result in an increase in 5-HT levels within the brain. An increase in 5-HT may lead to central fatigue, which causes a decrease in muscle force attributable to a decline in motoneuronal output.

BCAA supplementation before and after exhaustive exercise has been shown to decrease central fatigue 3, 12. One possible explanation is that BCAA might have an effect as a nitrogen donor or energy source in the skeletal muscle.

It has not been established whether BCAA treatment could inhibit the entry of tryptophan into the brain by the L-system transporter. Therefore, the aims in the present study were to establish whether inhibition of the L-system transporter (1) combats central fatigue; (2) reflects a decrease of tryptophan uptake and 5-hydroxytryptophan (5-HTP) synthesis.

The concentration of plasma free tryptophan is controlled by albumin binding to tryptophan which, in turn, is modulated by the displacement of tryptophan from albumin by fatty acids. Thus, an increase in the plasma concentration of fatty acids due to, for example, exhaustive exercise, makes more free tryptophan available. In post-operative recovery in elderly patients there was a decrease of the binding affinity of tryptophan to albumin and an increase in free tryptophan [19]. Accordingly, the provision of albumin may also inhibit uptake of plasma free tryptophan into the brain.

After fatigue, nagase analbuminaemic rats (NAR) showed enhanced tryptophan, 5-HTP and 5-HT concentrations in isolated, striatal synaptosomes [19]. In respect to this, the present studies investigated the effect on the inhibition of tryptophan uptake in the striatal synaptosomes after injecting albumin into NAR.

Section snippets

Materials and methods

Female analbuminaemic rats with a genetically controlled lack of plasma albumin (NAR, Japan SLC Inc.), 210–255 g were used. The animals were exposed to 12 h of light daily (0700–1900 h), at a temperature of 22°C.

NAR were acclimatized to running on a treadmill, by training for 30 min (20 m/min, 7% gradient) four times a week for five weeks, between 1300 and 1500 h consistently. After completing training, all NAR treatment groups were exercised to exhaustion on a motorized treadmill (20 m/min, 7%

Results

After training for 5 weeks, NAR were exercised to exhaustion. There was a significant increase in the running time to exhaustion for the NAR group, which received BCAA or BCH treatments, compared with those which received saline treatment (Table 1). Simultaneously, the concentrations of tryptophan, 5-HTP, 5-HT and 5-HIAA in striatal synaptosomes were measured immediately after running to exhaustion: the values for the BCAA group differed from saline treatment in terms of tryptophan and 5-HTP

Discussion

In the NAR, it would be expected that the free tryptophan levels would be high so that the free tryptophan/BCAA ratio in plasma would also be high. Despite training, there is considerable variation in the individual ability of NAR to run to fatigue, as shown by the ranges in Table 1. Nevertheless, there was a significantly prolonged running time in those NAR which received BCH and BCAA treatments. With respect to L-system inhibition, any effect of improving fatigue by BCH treatment was masked

Acknowledgements

Supported by grant from the Tezukayama Gakuen Foundation. The authors would like to thank Mr. H. Wada and Ms. A. Matsuyama for helpful preparation of the manuscript.

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ArticlesDiminished central fatigue by inhibition of the L-system transporter for the uptake of tryptophan

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

J. Affect. Disord.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Med. Metabol. Biol.

Pharmacol. Biochem. Behav.

Brain Res. Bull.

Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue

Acta Physiol. Scand.

Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat

Acta Physiol. Scand.

Influence of ingesting a solution of branched-chain amino acids on perceived exertion during exercise

Acta Physiol. Scand.

Articles
Diminished central fatigue by inhibition of the L-system transporter for the uptake of tryptophan