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Sci Rep. 2017 Aug 9;7(1):7677. doi: 10.1038/s41598-017-08055-1.

Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses.

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Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Japan.
Department of Neuropsychiatry, Faculty of Medicine, Tottori University, Yonago, Japan.
Department of Psychiatry, Nara Medical University School of Medicine, Kashihara, Japan.
Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan.
Watanabe Hospital, Tottori, Japan.
Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut, USA.


Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.

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