Dual roles of anesthetics in postoperative cognitive dysfunction: Regulation of microglial activation through inflammatory signaling pathways

Abstract

Postoperative cognitive dysfunction (POCD) is a prevalent clinical entity following surgery and is characterized by declined neurocognitive function. Neuroinflammation mediated by microglia is the essential mechanism of POCD. Anesthetics are thought to be a major contributor to the development of POCD, as they promote microglial activation and induce neuroinflammation. However, this claim remains controversial. Anesthetics can exert both anti- and pro-inflammatory effects by modulating microglial activation, suggesting that anesthetics may play dual roles in the pathogenesis of POCD. Here, we review the mechanisms by which the commonly used anesthetics regulate microglial activation via inflammatory signaling pathways, showing both anti- and pro-inflammatory properties of anesthetics, and indicating how perioperative administration of anesthetics might either relieve or worsen POCD development. The potential for anesthetics to enhance cognitive performance based on their anti-inflammatory properties is further discussed, emphasizing that the beneficial effects of anesthetics vary depending on dose, exposure time, and patients’ characteristics. To minimize the incidence of POCD, we recommend considering these factors to select appropriate anesthetics.

TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3‐mediated A1 differentiation of astrocytes

“…POCD is a disease with complex etiology. Although POCD has been researched for decades, with accumulation of substantial animal models and clinical studies, its pathogenesis and pathophysiology remain unclear, which may be associated with inflammation caused by postoperative trauma 16,17 . Recently, reactive RAs have been reported to be classified into types A1 and A2 similar to the microglia cells 18 .…”

“…Although POCD has been researched for decades, with accumulation of substantial animal models and clinical studies, its pathogenesis and pathophysiology remain unclear, which may be associated with inflammation caused by postoperative trauma. 16 , 17 Recently, reactive RAs have been reported to be classified into types A1 and A2 similar to the microglia cells. 18 RAs‐A1 upregulate a variety of synaptic destructive trophic factors to elevate the expressions of inflammatory cytokines, while RAs‐A2 upregulates neurotrophic factors to promote the neuronal and synaptic repair.…”

Neurosteroids and their potential as a safer class of general anesthetics

“…Although the pathogenesis of PND remains unknown, neuroinflammation caused by surgical trauma or pain and manifest as over-activation of microglia is a proposed mechanism [ 101 – 103 ]. While it is unclear whether commonly used anesthetics directly cause or exacerbate neuroinflammation [ 104 – 107 ], there is substantial evidence that NS attenuate neuroinflammation. Indeed, NS are being developed as treatments for a variety of neurodegenerative disorders, based on their ability to regulate neuroinflammation (Table 1 ).…”

Effect of General Anesthetic Agents on Microglia

“…In addition to receptors that sense physiological occurrences, microglia express a variety of pattern recognition receptors (PRRs) including toll-like receptors (TLRs), NOD-like receptors, and C-type lectin receptors, which can transmit inflammatory information by recognizing pathogen-associated molecular patterns (PAMPs) or tissue damage-associated molecular patterns (DAMPs) [ 9 ]. By recognizing anesthetic drug-sensitive PRRs, GAAs also promote changes in microglial cell type and function and increase or mitigate the release of inflammatory factors [ 10 ].…”