Abstract
Post-sepsis cognitive impairment is one of the major sequelae in sepsis survivors. Its prevention remains clinically challenging. Here we tested the effects and underlying mechanisms of exogenous β-hydroxybutyrate (BHB) on post-sepsis cognitive impairment. We found that subcutaneous administration of BHB increased survival and body weight recovery of sepsis mice and improved learning and memory of sepsis surviving mice in a cecal ligation and perforation-induced sepsis model. Additionally, the improvement of learning and memory of sepsis surviving mice was still detected even if BHB was administrated at the late stage of sepsis. In contrast, glucose solution did not show similar effects. Mechanistically, subcutaneous administration of BHB increased the BHB level of hippocampus, and limited neuroinflammation and neuroplasticity damage in sepsis mice. Intracerebroventricular administration of BHB also alleviated neuroinflammation and cognitive impairment of sepsis surviving mice. In the coculture of neurons, astrocytes, and BV2 cells (a microglial cell line), knocking down the expression of microglial HCA2 (BHB receptor) via a specific shRNA reduced the protection of BHB to lipopolysaccharide-induced inflammatory response and neuron damage more significantly than knocking down neuronal MCT2 (BHB transporter). These data showed that (1) BHB was a potential pharmacological adjunct treatment for prevention of post-sepsis cognitive impairment and (2) inhibiting neuroinflammation via HCA2 was an important mechanism.
Highlights
Post-sepsis cognitive impairment is one of the major sequelae in sepsis survivors and affects 12.5-21% [1]
The microglia activation percentages in CA1 and dentate gyrus of the cecal ligation and perforation (CLP)+NS group were obviously higher than those of the sham +NS group on the 12th day after CLP (p
We aimed to investigate the effects and underlying mechanisms of exogenous β-hydroxybutyrate (BHB) on post-sepsis cognitive impairment with the ultimate goal of developing a pharmacological adjunct treatment for post-sepsis cognitive impairment
Summary
Post-sepsis cognitive impairment is one of the major sequelae in sepsis survivors and affects 12.5-21% [1]. High prevalence of post-sepsis cognitive impairment remains an important problem in sepsis survivors, calling for new, simple and effective prevention methods. In addition to its classical role of being an alternative energy source, recent studies have shown that BHB could regulate innate immune response via suppressing activation of NLRP3 inflammasome [5]. We think that exogenous BHB may be useful in the prevention of post-sepsis cognitive impairment. We detected the effects and underlying mechanisms of exogenous BHB on post-sepsis cognitive impairment. BHB administration significantly limited neuroinflammation and neuroplasticity damage of sepsis mice. BHB administration limited lipopolysaccharides-induced neuron damage and inflammatory response via HCA2 and MCT2 in vitro. These data showed that BHB administration could prevent post-sepsis cognitive impairment
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