Evaluation of the antidepressive property of β-hydroxybutyrate in mice

Abstract

β-hydroxybutyrate, a ketone body metabolite, has been shown to suppress depression-like behavior in rodents. In this study, we examined its antidepressive property in acute and chronic administration modes in mice by using forced swim test and tail suspension test. Results showed that the decrease effect of β-hydroxybutyrate (300 mg/kg) on immobility time in the tail suspension test and forced swim test in stress-naive mice began to be significant at day 11. In a dose-dependent experiment, β-hydroxybutyrate treatment (11 days) showed significant antidepressant activities at the dose of 200 and 300 mg/kg. Unlike fluoxetine, β-hydroxybutyrate treatment (300 mg/kg) showed no antidepressant activities in the acute (1 hour before the test) and three times administration mode within 24 hours (1, 5, and 24 hours before the test). But in a co-administration mode, β-hydroxybutyrate (100 mg/kg) -fluoxetine (2.5 mg/kg) co-administration exhibited an obvious antidepressant activity in the tail suspension test and forced swim test. Further analysis showed that the antidepressant effects of β-hydroxybutyrate and fluoxetine were not associated with the change in mouse locomotor activity. Furthermore, both chronic β-hydroxybutyrate treatment and β-hydroxybutyrate-fluoxetine co-treatment suppressed chronic unpredictable stress-induced increase in immobility time in the tail suspension test and forced swim test as well as chronic unpredictable stress-induced decrease in mouse body weight. Taken together, these results indicate that β-hydroxybutyrate (1) needs a relatively long time to show comparable behavioral activity to that of fluoxetine in assays that are sensitive to the behavioral effects of established antidepressant compounds and (2) can augment the antidepressant action of a sub-therapeutic dose of fluoxetine.

Acute and chronic effects of oral administration of a medium‐chain fatty acid, capric acid, on locomotor activity and anxiety‐like and depression‐related behaviors in adult male C57BL/6J mice

“…The BHB is one of the ketone bodies converted from fats and fatty acids. It has been recently reported that BHB induces BDNF expression in cortical neurons, 40 inhibits hippocampal neuroinflammation, 14 and has an antidepressant‐like behavioral effect 14,15 . In this study, acute injection of low‐dose C10 produced no significant differences in plasma BHB levels between treatment groups.…”

“…It has been recently reported that BHB induces BDNF expression in cortical neurons, 40 inhibits hippocampal neuroinflammation, 14 and has an antidepressant-like behavioral effect. 14,15 In this study, acute injection of low-dose C10 produced no significant differences in plasma BHB levels between treatment groups. Our results showed that the acute behavioral effects of low-dose C10 were not associated with plasma BHB levels.…”

“…Finally, in Experiment 3, to examine behavioral effects of repeated administration of C10 at the lower doses (0.3 and 3.0 mmol/kg), mice were administered with C10 once a day for 3 weeks and were subjected to behavioral tests without C10 administration immediately before the tests. Fatty acids are rapidly metabolized to ketone bodies, such as beta‐hydroxybutyrate (BHB), which have been suggested to regulate anxiety‐like and depression‐related behaviors 14,15 . Thus, plasma BHB levels were measured from blood samples collected 30 minutes after oral gavage of C10 and were also analyzed approximately 24 hours after the last oral administration of C10 in Experiment 3 to examine the involvement of possible changes in ketone levels after C10 administration in the regulation of behaviors.…”

“…Fatty acids are rapidly metabolized to ketone bodies, such as beta-hydroxybutyrate (BHB), which have been suggested to regulate anxiety-like and depressionrelated behaviors. 14,15 Thus, plasma BHB levels were measured from blood samples collected 30 minutes after oral gavage of C10 and were also analyzed approximately 24 hours after the last oral administration of C10 in Experiment 3 to examine the involvement of possible changes in ketone levels after C10 administration in the regulation of behaviors.…”

On the nutritional and therapeutic effects of ketone body d-β-hydroxybutyrate

“…Furthermore, endogenous NLRP3 inhibition by d-3HB alleviated stress-induced anxiety and post-traumatic stress disorder (PTSD) (Yamanashi et al 2017(Yamanashi et al , 2020. d-3HB also promoted the effect of a subtherapeutic dose of an anti-depressant drug, which led to suppression of chronic unpredictable stress-induced increase in immobility time and reduction in body weight in rat studies (Pan et al 2020).…”