Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis

Abstract

Background

Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice.

Methods

A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated.

Results

Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway.

Conclusions

Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Introduction

Postoperative cognitive dysfunction (POCD) is defined as long-term cognitive impairment that occurs weeks to months after surgery. The incidence of POCD in major non-cardiac surgery patients aged > 65 years has been reported to be 25.8% at one week and 9.9% at three months postoperatively [1,2,3,4]. Although the exact pathophysiology behind the development of POCD is not fully understood, it is believed to be caused by the following mechanisms: blood–brain barrier damage, neuroinflammatory responses, abnormal synaptic transmission, neuronal apoptosis, oxidative stress, abnormal amyloid-beta deposition and Tau protein phosphorylation, polymorphisms of the apolipoprotein E gene, and abnormal energy metabolism [5,6,7]. In addition, long-standing geriatric POCD can be a consequence of Alzheimer’s disease, decreasing quality of life and imposing a significant economic burden on families and society [8]. With the growing elderly population worldwide, the need for surgical procedures is rapidly increasing, leading to a high prevalence of POCD. However, our understanding and diagnosis of POCD still encounter numerous challenges. Therefore, there is an urgent need to explore the pathogenesis of POCD from a new perspective and identify new targets for drug therapy.

Itaconate is an endogenous metabolite derived from the tricarboxylic acid cycle and is produced by cis-aconitic acid decarboxylation catalyzed by immune response gene 1 (IRG1) in the mitochondrial matrix [9]. Itaconate is an immunoregulatory metabolite that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In recent years, it has been shown that itaconate can attenuate neuroinflammation and exert dopamine neuroprotection in Parkinson’s disease through inhibition of NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome. The mechanism of this neuroprotective effect of itaconate involves the scaffold protein p62/Nrf2/Heme oxygenase 1 (HO-1)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis pathway in microglia [

Availability of data and materials

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number (s) can be found below: NCBI BioProject (https://www.ncbi.nlm.nih.gov/sra/PRJNA1078590) and MetaboLights repository (https://www.ebi.ac.uk/metabolights/editor/study/MTBLS9593). Other datasets used and analyzed during this study can be obtained from the corresponding author upon reasonable request.