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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / administration & dosage
  • 3-Hydroxybutyric Acid / pharmacology*
  • Animals
  • Anxiety
  • Behavior, Animal
  • Biomarkers
  • Cytokines / metabolism
  • Depression
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Inflammation / drug therapy
  • Inflammation / etiology*
  • Inflammation / metabolism*
  • Inflammation / psychology
  • Male
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • Rats
  • Stress, Physiological*
  • Stress, Psychological*


  • Biomarkers
  • Cytokines
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • 3-Hydroxybutyric Acid