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Open AccessArticle

Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress

Research Laboratories for Health Science & Food Technologies, Kirin Holdings Company Ltd, Kanazawa-ku, Yokohama-shi, Kanagawa 236-0004, Japan
Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Japan Agency for Medical Research and Development (AMED)-CREST, Chiyoda-ku, Tokyo 100-0004, Japan
Author to whom correspondence should be addressed.
Nutrients 2019, 11(9), 2161;
Received: 3 August 2019 / Revised: 25 August 2019 / Accepted: 29 August 2019 / Published: 9 September 2019
(This article belongs to the Special Issue Effect of Bioactive Peptides on Human Health)
The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we discovered that leucine–histidine (LH) dipeptide suppressed activation of primary microglia. The effects of LH dipeptide orally administered were measured using tail suspension test (TST) in mice injected with lipopolysaccharide and social interaction test in mice received social defeat stress. LH dipeptide reduced pro-inflammatory cytokines upon stimulation in microglia. Orally administered LH dipeptide was delivered to the brain and suppressed the production of pro-inflammatory cytokines in the brain and concomitant depression-like behavior in the TST. Moreover, oral administration of LH dipeptide suppressed the induction of depression- and anxiety-like behaviors induced by repeated social defeat stress. These results indicate that LH dipeptide suppressed the activation of microglia and ameliorated depression-associated emotional disturbances. Further, we found that LH dipeptide was abundant in various fermented products. Together with previous epidemiological reports that daily intake of these fermented foods is negatively associated with the incidence of psychiatric diseases, our findings suggest that food rich in LH dipeptide may improve mental health. View Full-Text
Keywords: antidepressant; cytokine; dipeptide; inflammation; microglia antidepressant; cytokine; dipeptide; inflammation; microglia
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Ano, Y.; Kita, M.; Kitaoka, S.; Furuyashiki, T. Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress. Nutrients 2019, 11, 2161.

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