Ketone Supplementation Decreased Lipopolysaccharide-Generated Anxiety-like Behavior in Female WAG/Rij Rats

Background/Objectives: Inflammatory processes, including elevated pro-inflammatory cytokines such as interleukin 1β (IL-1β), have been implicated in the pathophysiology of anxiety disorders. The ketone body β-hydroxybutyrate (βHB) was shown to mitigate inflammatory processes induced by lipopolysaccharide (LPS) administration. It was also suggested that exogenous ketone supplements, such as ketone esters (KEs) and ketone salts (KSs), can decrease anxiogenic effects through increased blood ketone levels in the body (ketosis) in preclinical animal models. Methods: Thus, we investigated whether standard rodent food supplemented with KEKS (KEKS food: mix of a KE R/S-1,3-butanediol-acetoacetate diester and a KS Na⁺- and Ca²⁺- R/S-βHB salt in 1:1 ratio) for 7 days can alleviate the intraperitoneal (i.p.) 1 mg/kg LPS-generated anxiogenic effect in female Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. For the evaluation of anxiogenic effects, the light-dark box (LDB) test was used. Results: KEKS food significantly increased the blood R-β-hydroxybutyrate (R-βHB) level and decreased the blood glucose level compared to the baseline. Moreover, the LPS significantly (i) decreased the time spent in the light compartment, the number of chamber transitions, the number of re-entries to the light compartment and the number of rearing in the light compartment, and also (ii) increased the time of latency to the first re-entry to the light compartment compared to control. Nevertheless, KEKS food treatment abolished LPS-generated anxiety-like behavior. Conclusions: The current study demonstrated that a 7-day KEKS-supplemented diet can increase blood R-βHB levels and abolish acute LPS administration-evoked increases in anxiety levels in female WAG/Rij rats. Moreover, our results support the important role of neuroinflammation in pathological processes resulting in anxiety. Thus, these results suggest that exogenous ketone supplement-generated ketosis may be a promising therapeutic tool in the treatment of inflammatory process-mediated diseases, such as anxiety disorders.