Medium-Chain Triglyceride Administration Induces Antidepressant Effects in Animal Models by Increasing Beta-Hydroxybutyrate Levels.

Abstract

Background: Inflammation is believed to contribute to the pathophysiology of depression, with increased levels of inflammatory cytokines, such as interleukin-1β (IL-1β), observed in patients. Depression is also common in individuals with chronic inflammatory diseases. IL-1β disrupts synaptic transmission and reduces neurogenesis in the hippocampus, playing a crucial role in depression development. Our prior research found that stress activates microglia in the brain to produce IL-1β via the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Additionally, β-hydroxybutyrate (BHB), an endogenous ketone body, alleviates stress-induced depression by inhibiting NLRP3 activation and IL-1β production. However, BHB's poor bioavailability limits its effectiveness. Medium-chain triglycerides (MCTs) can increase blood BHB levels, making them a potential treatment for stress-induced depression.

Methods: We tested MCT in two animal models: social defeat (SD) in mice and chronic unpredictable stress (CUS) in rats. MCT was orally administered to both groups to assess blood BHB levels. Behavioral tests, including the forced swim test (FST), were performed, and brain tissue was analyzed for IL-1β levels and spine density.

Results: MCT administration increased blood BHB levels 7-11 times within 1 hour. In the SD model, MCT significantly reduced immobility time in the FST, suggesting antidepressant effects. While the CUS model showed no significant change, a trend toward reduced immobility time was observed. MCT treatment also reduced stress-induced IL-1β levels in the rat hippocampus, although spine density remained unchanged.

Conclusion: MCT appears to alleviate stress-induced depression-like behaviors, likely through the suppression of IL-1β in the hippocampus. Owing to its ease of oral administration, MCT may offer a practical treatment for stress-related depression.