Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit - PubMed (original) (raw)

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Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit

Masatoshi Yamashita. Int J Tryptophan Res. 2020.

Abstract

Central fatigue leads to reduced ability to perform mental tasks, disrupted social life, and impaired brain functions from childhood to old age. Regarding the neurochemical mechanism, neuroactive tryptophan metabolites are thought to play key roles in central fatigue. Previous studies have supported the "tryptophan-serotonin enhancement hypothesis" in which tryptophan uptake into extensive brain regions enhances serotonin production in the rat model of exercise-induced fatigue. However, serotonin was transiently released after 30 minutes of treadmill running to exhaustion, but this did not reflect the duration of fatigue. In addition, as the vast majority of tryptophan is metabolized along the kynurenine pathway, possible involvement of the tryptophan-kynurenine pathway in the mechanism of central fatigue induction has been pointed out. More recently, our study demonstrated that uptake of tryptophan and kynurenine derived from the peripheral circulation into the brain enhances kynurenic acid production in rat brain in sleep deprivation-induced central fatigue, but without change in serotonin activity. In particular, dynamic change in glial-neuronal interactive processes within the hypothalamus-hippocampal circuit causes central fatigue. Furthermore, increased tryptophan-kynurenine pathway activity in this circuit causes reduced memory function. This indicates a major potential role for the endogenous tryptophan-kynurenine pathway in central fatigue, which supports the "tryptophan-kynurenine enhancement hypothesis." Here, we review research on the basic neuronal mechanism underlying central fatigue induced by neuroactive tryptophan metabolites. Notably, these basic findings could contribute to our understanding of latent mental problems associated with central fatigue.

Keywords: Central fatigue; glial-neuronal interactions; neuroactive tryptophan metabolites.

© The Author(s) 2020.

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Conflict of interest statement

Declaration of Conflicting Interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Figure 1.

Factors affecting each type of fatigue. Fatigue is mainly divided into 3 types: central fatigue, peripheral fatigue, and infection fatigue. Because of their neurochemical mechanisms, recovery from central fatigue and infection fatigue is more difficult without sufficient rest and supplements (or medicines) relative to peripheral fatigue.

Figure 2.

Figure 2.

The neuroactive tryptophan pathway and metabolites. In mammals, as only about 5% of tryptophan is catabolized via the serotonin pathway, the vast majority of tryptophan is metabolized in the kynurenine pathway, which is the precursor pathway for the synthesis of the neuroinhibitory molecule, kynurenic acid, and neurotoxic molecule, quinolinic acid. Is the rate of the kynurenine pathway of tryptophan metabolism involved in central fatigue? If the tryptophan-kynurenine pathway is enhanced during central fatigue, does it lead to a reduction in cognitive functions and severe fatigue?

Figure 3.

Figure 3.

School refusal children showed higher levels of central fatigue and sleep derangement. (A and B): Compared with healthy control children, school refusal children showed a significant shift in the midpoint of sleep and lower sleep quality. (C and D): Moreover, induction of central fatigue and decreased cognition were significantly greater in school refusal children. The derangement of sleep and induction of central fatigue were higher for the school refusal children. *P < .05, **P < .01.

Figure 4.

Figure 4.

Central fatigue becomes more severe as sleep disturbance progresses. (A): In schoolchildren, central fatigue was positively correlated with disturbance of sleep rhythm (r = 0.61, P = .001). (B): In schoolchildren, central fatigue was negatively correlated with sleep efficiency (r = −0.50, P = .01). These results indicate that higher level of central fatigue is influenced by sleep disturbance.

Figure 5.

Figure 5.

The uptake of peripheral tryptophan by the brain. Tryptophan binds to albumin in the blood under normal conditions. Non-esterified fatty acids (NEFA) also compete for the same binding site. An increase in the levels of NEFA results in the dissociation of albumin and tryptophan during exercise-induced fatigue and postoperative-induced fatigue. Then, free tryptophan is rapidly taken into the brain via system L transporter located on the surface of the blood-brain barrier, and thus leading to enhanced serotonin synthesis in the brain by the enzymatic activity of tryptophan hydroxylase 2. 5-HIAA indicates 5-hydroxyindoleacetic acid; LAT-1, L-type amino acid transporter 1.

Figure 6.

Figure 6.

The effect of tryptophan receptor agonist administration on biobehavioral activities. (A and B): Rats administered DLA had lower spontaneous locomotor activities in the open field than rats administered saline. (C): Serotonin concentration in the hypothalamus decreased in rats injected with DLA compared with rats injected with saline. This result indicates that tryptophan receptor agonist induces the reduction of locomotor activity and serotonin level, although most studies have reported that serotonin activity in the brain is associated with central fatigue. It is possible that tryptophan-serotonin pathway is not involved in central fatigue. DLA indicates

d

,

l

-β-(1-naphthyl)alanine.

Figure 7.

Figure 7.

Disruption of the blood-brain barrier (BBB) by sleep deprivation–induced central fatigue. The breakdown of the BBB can be estimated by quantification of extravasated Evans Blue in the brain. Using this method, extravasated Evans Blue content in the whole brain increased in central fatigue induced by (A) chronic sleep disorder (CFSD) rats compared with (B) healthy rats. This result indicates that central fatigue could lead to increased BBB permeability, suggesting barrier breakdown. Perhaps, tryptophan and other substances can freely enter the brain without the assistance of some transporter.

Figure 8.

Figure 8.

Metabolism of tryptophan to kynurenine during central fatigue. Tryptophan is catabolized along the kynurenine pathway by tryptophan dioxygenase (TDO) or indoleamine dioxygenase in the liver, and then crosses the blood-brain barrier (BBB) to be rapidly taken up in the brain. Also, tryptophan may be directly metabolized to kynurenine by the enzymatic activity of TDO in the brain. In central fatigue, tryptophan and kynurenine enter the brain via the BBB in a synergetic manner. LAT-1 indicates L-type amino acid transporter 1.

Figure 9.

Figure 9.

The role of the fatigue circuit: from blood to brain. There are 3 stages of central fatigue induction. Stage 1 is marked by synergetic transfer of tryptophan and kynurenine from blood to brain. Stage 2 is indicated by the rise of brain tryptophan and kynurenine to excessive levels and detection of tryptophan-kynurenic acid pathway activity at the glial-neuronal interactive level within the hypothalamus-hippocampal circuit. Stage 3 is the impairment of cognitive functions. The fatigue circuit includes the tryptophan-kynurenine-kynurenic acid pathway signals generated at neuronal-neuronal and glial-neuronal synapses between the peripheral and central nervous systems. Enhancement of pathway activity triggers cognitive dysfunction. LAT-1 indicates L-type amino acid transporter 1.

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