Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression
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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.
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Inflammasome activation has an essential role in the progression of several neurological disorders like MS, AD, PPD, and NPS.
“In the CNS, inflammasome activation has been mainly linked to neuroinflammatory conditions. As example, it has an essential role in the progression of several neurological disorders like MS, AD, PPD, and NPS (132, 193–197).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [196]
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“P .001 for comparisons between nonstress + PBS vs CUS + PBS, nonstress + PBS vs CUS + BHB, nonstress + BHB vs CUS + PBS, and nonstress + BHB vs CUS + BHB. Error bars represent the standard error of the mean (SEM).”
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- Authors
- Kajitani, N., Iwata, M., Miura, A., Tsunetomi, K., Yamanashi, T., Matsuo, R., Nishiguchi, T., Fukuda, S., Nagata, M., Shibushita, M., Yamauchi, T., Pu, S., Shirayama, Y., Watanabe, K., & Kaneko, K.
- Affiliations
- Tottori University (JP)
- Nara Medical University (JP)
- Teikyo University Chiba Medical Center (JP)
- Watanabe Hospital Tottori Japan
- Corresponding author
- Iwata, Masaaki
- ORCID
- Venue
- Neuropsychopharmacology Reports
- Publisher
- Wiley
- Published
- 2020-03-03
- Volume
- 40
- Issue
- 2
- Pages
- 157-165
- ISSN
- 2574-173X (ISSN-L)
- PMC
- PMC7722664
- OpenAlex
- W3009937427
- Cited by
- 49
- References
- 56
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 6
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neuropsychopharmacology Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Tottori University research result repository (Tottori University) (submittedVersion)
- Funders
- GlaxoSmithKline foundation
- SENSHIN Medical Research Foundation
- Japan Society for the Promotion of Science (JP15K19729, JP17K10273)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- beta-hydroxybutyrate, depression, prefrontal cortex, neuroinflammation, NLRP3 inflammasome, chronic unpredictable mild stress, antidepressant effects, IL-1β, TNF-α, corticosterone, hypothalamic-pituitary-adrenal axis, ketone bodies, forced swim test
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Antidepressive Agents, Corticosterone, Depression, Disease Models, Animal, Infusion Pumps, Male, Microinjections, Rodentia, Rats, Sprague-Dawley, Prefrontal Cortex, 3-Hydroxybutyric Acid, Rats
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