Aims: Neuroinflammation is deeply related to the pathophysiology of depression. Beta-hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti-inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm.
Methods: BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21 days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro-inflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured.
Results: BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF-α in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti-inflammatory mechanisms, and can improve hypothalamus-pituitary-adrenal axis responses.
Conclusion: BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro-inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.
Keywords: NLRP3; beta-hydroxybutyrate; depression; inflammasome; prefrontal cortex; stress.
© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.