Quinolinic Acid Decreases Mental Activity in Mice by Damaging Brain Neurons through the Activation of N-methyl-D-aspartate Receptors: Proposed Relationship to Human Mental Fatigue

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概要

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• It is generally known that many psychological factors, such as stress or insomnia, cause mental fatigue. However, the detailed mechanisms underlying mental fatigue have not been clarified. We speculated that mental fatigue may be caused by neuronal brain damage through the activation of N-methyl-D-aspartate (NMDA) receptors by quinolinic acid (QUIN), one of the metabolites of tryptophan in the kynurenine pathway. In the present study, we tested this hypothesis in mice using a home cage equipped with a running wheel; voluntary wheel-running reflected mental activity. In normal mice, wheel-running activity was not affected by intraperitoneal administration of QUIN, but it was significantly decreased by intracerebroventricular administration of QUIN. In restraint stress-loaded mice, whose blood-brain barriers were weakened, wheel-running activity was significantly decreased by intraperitoneal administration of QUIN, and this effect was inhibited by memantine hydrochloride (MEM), an NMDA receptor antagonist. Intraperitoneal administration of lipopolysaccharide (LPS) induced a decrease in wheel-running activity and a concomitant increase in blood and brain QUIN levels. MEM inhibited the LPS-induced decrease in wheel-running activity, but it did not affect the increase in blood and brain QUIN levels. The number of hippocampal neurons was significantly decreased by LPS treatment, and this effect was inhibited by MEM. These results suggest that QUIN, which is produced via tryptophan metabolism, decreases mental activity in mice by damaging brain neurons through the activation of NMDA receptors. This finding supports, at least in part, our hypothesis that the same mechanism contributes to causing human mental fatigue.

• 公益社団法人　日本薬学会の論文

著者

• Morimoto Yasuo

  Kampo Research Laboratories, Kracie Pharma, Ltd.

• Zhang Qian

  Kampo Research Laboratories, Kracie Pharma, Ltd.

• Adachi Koji

  Kampo Research Laboratories, Kracie Pharma, Ltd.

関連論文

• Quinolinic Acid Decreases Mental Activity in Mice by Damaging Brain Neurons through the Activation of N-methyl-D-aspartate Receptors: Proposed Relationship to Human Mental Fatigue
• Increased Blood Quinolinic Acid after Exercise in Mice: Implications for Sensation of Fatigue after Exercise
• Effects of Memantine, an N-Methyl-D-aspartate Receptor Antagonist, on Fatigue and Neuronal Brain Damage in a Rat Model of Combined (Physical and Mental) Fatigue

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