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Abstract
Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.
Highlights
Postoperative delirium (POD) is a frequent manifestation of acute cerebral dysfunction in older adults after surgery under general anesthesia that usually peaks between 1 and 3 days after the operation (Al Tmimi et al, 2015; Oh and Park, 2019)
We performed the immunofluorescence staining of Iba1 (Figure 1A), a recognized maker for microglia, to detect the microglia activation and found there’s significant increased Iba1 + cell numbers (Figure 1B) and microglial intensity (Figure 1C) in sevoflurane mice hippocampus
Postoperative delirium is a prevalent complication that is frequently observed after surgery and general anesthesia (Sieber et al, 2018; Kinjo et al, 2019)
Summary
Postoperative delirium (POD) is a frequent manifestation of acute cerebral dysfunction in older adults after surgery under general anesthesia that usually peaks between 1 and 3 days after the operation (Al Tmimi et al, 2015; Oh and Park, 2019). It has been reported that POD can arise in the same individuals with overlapping risk factors, leading to a common underlying neuropathogenesis of postoperative cognitive dysfunction (POCD) (Fong et al, 2009; Schmitt et al, 2012). The available evidence demonstrates that central nervous system dysfunction caused by anesthesia during surgery that further leads to neurocognitive disorders is a main factor related to POD (Evered and Silbert, 2018). The original validation study showed that individuals who underwent general anesthesia had a 40% higher risk of incident dementia than those who were not hospitalized for surgery (Ehlenbach et al, 2010). The underlying mechanisms by which general anesthesia induces POD remain largely unclear
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