Lactate improves postoperative cognitive function through attenuating oxidative stress and neuroinflammation in aged mice via activating the SIRT1 pathway

Abstract

Postoperative cognitive dysfunction (POCD) is a recognized clinical phenomenon characterized by cognitive impairment in patients following anesthesia and surgery, especially in the elderly. However, the pathogenesis of POCD remains unclear. In the last decades, lactate's neuroprotective properties have been increasingly mentioned. The study tested the hypothesis that lactate may attenuate the cognitive impairment induced by anesthesia and surgery in aged mice through SIRT1-dependent antioxidant and anti-inflammatory effects. We used 18-month-old C57BL/6 mice to establish the POCD animal model by exploratory laparotomy with isoflurane anesthesia. For the interventional study, mice were administered lactate, with or without the potent and selective SIRT1 inhibitor EX-527. Behavioral tests including open field (OF), Y maze and fear conditioning (FC) tests were performed from 4 to 7 days after anesthesia and surgery. Immunofluorescence staining and Western blot were employed to assess oxidative damage, activation of microglia and astrocytes, levels of proinflammatory cytokines, and the expression of plasticity-related proteins. Lactate treatment can ameliorate oxidative stress, neuroinflammation, and the decreased levels of plasticity-related proteins induced by anesthesia and surgery, ultimately improving cognitive impairment in aged mice. However, co-treatment with lactate and EX-527 diminished the beneficial effects. Our study indicates that the mechanisms underlying neuroprotective properties of lactate might be related to its antioxidant and anti-inflammatory effects, and improvement of hippocampal synaptic plasticity through activation of SIRT1 pathway.

Keywords: Cognitive dysfunction; Lactate; Neuroinflammation; Oxidative stress; SIRT1; Surgery.