Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model.

Accumulating evidence suggests that elevated inflammation contributes to the pathophysiology of post-traumatic stress disorder (PTSD) and that anti-inflammatory drugs might be a new treatment strategy for PTSD. It has been reported that beta-hydroxybutyrate (BHB), one of the main ketone bodies produced, can have an anti-inflammatory and antidepressant effect. Here, we investigated the potential anti-anxiety and anti-inflammatory effects of BHB using a rodent PTSD model, induced by single prolonged stress (SPS). Male, Sprague-Dawley rats were employed in this study. Repeated administration of BHB attenuated SPS-induced anxiety-related behaviors evaluated by the elevated plus maze test. SPS increased the serum levels of TNF-α and IL-1ß. In contrast, BHB administration partially attenuated the increase of serum TNF-α. These findings demonstrate that BHB exerts its anxiolytic effects, possibly by inhibiting systemic TNF-α. Hence, BHB may be a novel therapeutic candidate for the treatment of PTSD.

Maternal immune activation induces sustained changes in fetal microglia motility.

Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression.

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 1ß (IL-1ß) 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.