Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses
Major depressive disorder (MDD) is characterized by depressed mood, anhedonia, low self-esteem, loss of motivation, sleep disruption, loss of appetite, and other cognitive symptoms1. Approximately 33% of patients with depression exhibit little or no improvement when treated with existing typical antidepressants, which commonly act on the monoaminergic systems2. Therefore, there is a need to develop novel treatments for depression.
Recent evidence has suggested that pro-inflammatory cytokines play a crucial role in the pathophysiology of MDD3, and that blood levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), are significantly higher in patients with MDD3, 4. Preclinical studies have revealed that both stress and IL-1β decrease neurogenesis in the adult hippocampus, and that this effect is associated with the development of depressive behaviors5. Moreover, inhibition of IL-1β by administration of IL-1β receptor antagonist or IL-1β receptor deletion abolishes both the anti-neurogenic and depressive behavioral effects of stress5,6,7.
Recently, we demonstrated that immobilization (IMM) stress elevates extracellular IL-1β levels in the adult hippocampus, and that antagonism of the purinergic type 2 X7 receptor (P2X7R), which is the upstream target of the IL-1β production cascade, inhibits the increase in IL-1β levels in the hippocampus, and reverses depressive behaviors induced by chronic unpredictable stress (CUS)8. We also revealed that peripheral administration of IL-1β neutralizing antibody blocks depressive-like behaviors induced by CUS8. These findings indicate that IL-1β plays a critical role in the development of depression, and that inhibition of IL-1β may represent a novel therapeutic strategy for the treatment of depression9.
The findings of the present study demonstrate that BHB treatment exerts antidepressant-like effects in a CUS-induced rat model of depression, and that BHB attenuates stress-induced increases in hippocampal levels of IL-1β. As IL-1β, which is thought to be tightly regulated by NLRP3 inflammasome, plays a critical role in stress-induced neuro-inflammation and in the development of depressive states, BHB may exert its antidepressant-like effects via blockade of NLRP3-induced increases in hippocampal levels of IL-1β. BHB is an endogenic NLRP3 inflammasome inhibitor, which is thought to be a safe and versatile physiologically active substance and therefore has some advantages for clinical applications. These results are critical for the development of new pharmacotherapeutic approaches that target neuro-inflammation in MDD.