PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders

Abstract

Background Clinical and animal studies demonstrated that neuroinflammation from anesthesia (sevoflurane) is the main contributor to cause perioperative neurocognitive disorders (PND). Recently, it was reported that microglia respond to hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which was the target of sevoflurane. Whether HCN channels are involved in the induction of neuroinflammation after sevoflurane exposure is still unclear. Results Sevoflurane exposure had increased cognitive dysfunction and anxiety-like behaviors in rats. Rats inhaled with sevoflurane had activated microglia and increased neuroinflammation (IL-1β, IL-6, and TNF-α) in the hippocampus. RNA sequencing identified 132 DEGs (86 up-regulated and 46 down-regulated DEGs [differentially expressed genes]) in the hippocampus of PND rats. RNA-sequencing also uncovered that sevoflurane exposure down-regulates HCN2 expression. Pathway and process enrichment analysis suggests DEGs are mainly enriched in regulation of system process, positive regulation of glutamate secretion, secretion, regulation of synaptic transmission, regulation of nervous system process, behavior, negative regulation of sodium ion transport, and learning or memory. We validated that sevoflurane exposure can down-regulate the levels of PEX5R/Trip8b (an interaction partner and auxiliary subunit of HCN channels) and HCN1-4 channels in the hippocampus of PND rats. We used immunofluorescence staining to identify that HCN2 co-labels with neurons (Neun), astrocytes (GFAP), and microglia (iba1). We observed that the co-labeling of HCN2 with neurons or microglia decreased in the hippocampus and cortex after sevoflurane exposure. Blocking HCN2 by ZD7288 treatment further activated microglia and aggravated sevoflurane exposure-induced anxiety-like behavior, cognitive impairment, and neuroinflammation. Conclusions We concluded that sevoflurane exposure can induce an increased level of neuroinflammation, microglial activation, cognitive dysfunction, and anxiety-like behaviors in rats. HCN2 channel, as the target of sevoflurane action, mediates this process. HCN2 might be a target for the treatment and prevention of sevoflurane-induced PND.

The changing of α5‐GABAA receptors expression and distribution participate in sevoflurane‐induced learning and memory impairment in young mice

“…Although, xiangdong Chen, et al. (2022) reported that in cognitive‐impaired rats inhaling sevoflurane, there is an upregulation of neuroinflammation (IL‐1β, IL‐6, and TNF‐α) in the hippocampus 55 . The effect of sevoflurane on the expression of inflammatory factors may be related to the concentration and duration of anesthesia, as well as organ specificity 56 .…”

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors

“…According to previous work, the i.c.v. injection site was located as: AP (anteroposterior) = −1.2 mm, ML (mediolateral) = 1.8 mm, and DV (dorsoventral) = 4.0 mm [ 15 ]. Then, following SIN establishment by sevoflurane exposure, these rats were assigned to two groups: the Sevo-IgG and Sevo-C1q groups.…”

Anesthesia-mediated neuroinflammatory sequelae in post operative cognitive dysfunction: mechanisms and therapeutic implications

“…As reviewed, this inflammasome mediates the secretion of proinflammatory cytokines such as IL-1β and IL-18. Similarly, exposure to sevoflurane has been shown to result in hippocampal microglial activation with elevated IL-1β, IL-6, and TNF-α, mediated through HCN2 channel inhibition (188). Specifically, sevoflurane resulted in downregulation in PEX5R/Trip8b-HCN2 channels in microglia and neurons while causing neuroinflammation in the rodent cortex and hippocampus.…”