Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses

Abstract

Neuro-inflammation has been shown to play a critical role in the development of depression. Beta-hydroxybutyrate (BHB) is a ketone body and has recently been reported to exert anti-inflammatory effects via inhibition of NLRP3 inflammasome. Here, we investigated the potential antidepressant and anti-inflammatory effects of BHB on rats exposed to acute and chronic stress. We examined the influence of repeated BHB administration on depressive and anxiety behaviors in a rodent model of chronic unpredictable stress (CUS). Additionally, the influence of acute immobilization (IMM) stress and single BHB administration on hippocampal interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were assessed. Repeated administration of BHB attenuated CUS-induced depressive- and anxiety-related behaviors. IMM stress increased levels of IL-1β in the hippocampus, while a single pre-administration of BHB attenuated this increase. Although no effect was observed on hippocampal TNF-α levels after 1 h of IMM stress, a single BHB pre-administration reduced hippocampal TNF-α. Our previous report showed that the release of IL-1β and TNF-α caused by stress is tightly regulated by NLRP3 inflammasome. These findings demonstrate that BHB exerts antidepressant-like effects, possibly by inhibiting NLRP3-induced neuro-inflammation in the hippocampus, and that BHB may be a novel therapeutic candidate for the treatment of stress-related mood disorders.

Metabolic regulation of NLRP3

“…In rat models of stress-induced neuronal inflammation, BHB attenuated hippocampal IL-1β production and reduced anxiety-and depression-related phenotypes. 54 BHB acting as an anti-inflammatory with causal anti-depressant effects further emphasizes a therapeutic role for potential BHB therapies.…”

BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer's disease

“…5XFAD mice show deficits in learning and memory at 4.5 month 31 and exhibit significant neuron loss at 9 month. 13 In another example, a 63-yearold sporadic AD patient treated with ketone monoester exhibited elevated plasma BHB and improvement in memory retrieval. Peripheral administration of 1.5 mM BHBA greatly improved learning ability and memory, as well as significantly reduced amyloid burden in the asymptomatic mouse model of AD.…”

“…10,11 Emerging data suggest that the ketogenic diet could also be useful in other neurodegenerative diseases including Alzheimer's and Parkinson's diseases (PD). 13 It could also protect dopaminergic neurons against inflammatory challenges both in vivo and in vitro in Parkinson's disease models. Interestingly, BHBA treatment exerted antidepressant-like effects in a depression rat model and attenuated stress-induced increases in levels of IL-1β in the hippocampus.…”

“…Interestingly, BHBA treatment exerted antidepressant-like effects in a depression rat model and attenuated stress-induced increases in levels of IL-1β in the hippocampus. 13 It could also protect dopaminergic neurons against inflammatory challenges both in vivo and in vitro in Parkinson's disease models. 14,15 The neuroprotective effect of BHBA has been shown to be mediated by hydroxycarboxylic acid receptor 2 (HCA2), also called BHBA by measuring the presence or absence of G protein-coupled receptor 109A (GPR109A).…”

β‐Hydroxybutyrate exacerbates lipopolysaccharide/d‐galactosamine‐induced inflammatory response and hepatocyte apoptosis in mice

“…The LPS/ d ‐Gal group and the BHB + LPS/ d ‐Gal group indicated Vehicle or BHB (80 mg/kg, dissolved in normal saline [NS]) were pretreated respectively 0.5 hours before LPS/ d ‐Gal exposure. The dose of BHB was chosen based on the previous reports and our preliminary experiment . The control group and the BHB group were injected intraperitoneally with the same volume NS and BHB, respectively.…”