Prefrontal cortex infusion of beta‐hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant‐like effects in a rodent model of depression
Open Access
- 3 March 2020
- journal article
- research article
- Published by Wiley in Neuropsychopharmacology Reports
- Vol. 40 (2), 157-165
- https://doi.org/10.1002/npr2.12099
Abstract
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
Funding Information
- GlaxoSmithKline foundation
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science (JP15K19729, JP17K10273)
This publication has 59 references indexed in Scilit:
- Effect of a hypertonic balanced ketone solution on plasma, CSF and brain beta-hydroxybutyrate levels and acid–base statusIntensive Care Medicine, 2013
- Neurobiology of chronic mild stress: Parallels to major depressionNeuroscience & Biobehavioral Reviews, 2012
- Proinflammatory cytokines in the prefrontal cortex of teenage suicide victimsJournal of Psychiatric Research, 2012
- D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's DiseasePLOS ONE, 2011
- Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic ratsBrain Research, 2011
- Structural and synaptic plasticity in stress-related disordersProgress in Neurobiology, 2011
- Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recoveryNeuroscience, 2009
- Cholinergic control of inflammationJournal of Internal Medicine, 2009
- IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stressProceedings of the National Academy of Sciences of the United States of America, 2008
- THE EFFECTS OF STRESSFUL LIFE EVENTS ON DEPRESSIONAnnual Review of Psychology, 1997