Abstract
Sevoflurane (SEV), a commonly used volatile anesthetic, has been shown to cause cognitive decline in diabetic rats by aggregating neuroinflammation in the hippocampus, but the underlying mechanisms are unknown. Recent evidence suggests that neuroinflammation could be a consequence of failure to resolve inflammation by specialized pro-resolving lipid mediators including resolvin D1 (RvD1). Here we first examined whether type 2 diabetes mellitus (DM) alters RvD1 proresolution pathway. Diabetic Goto-Kakizaki (GK) rats and non-diabetic Wistar rats received control or 2.6% SEV exposure for 4 h. Seven days after exposure, GK control rats, compared with Wistar control rats, had significantly lower RvD1 levels in plasma and CSF and decreased RvD1 receptor FPR2 expression in the hippocampus. SEV increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in Wistar rats but not in GK rats. We next examined whether RvD1 treatment of GK rats can prevent SEV-induced neuroinflammation and cognitive decline. GK rats received control, SEV or SEV and once-daily treatment with exogenous RvD1 (0.2 ug/kg, ip) for 7 days. RvD1 administration markedly increased RvD1 levels in plasma and CSF and FPR2 expression in the hippocampus in GK rats received SEV. Compared with GK control rats, GK rats received SEV exhibited shorter freezing times in trace fear conditioning task, which was accompanied by increased microglia activity and pro-inflammatory cytokine expression in the hippocampus. RvD1 administration attenuated SEV-induced increases in microglia activity and pro-inflammatory cytokine expression in the hippocampus, preventing cognitive decline in GK rats. Notably, neither SEV nor RvD1 altered metabolic parameters in GK rats. The results suggest that RvD1 proresolution pathway is impaired in the brain of diabetic GK rats. which may enhance the susceptibility to SEV, contributing to neuroinflammation and cognitive decline. Restoration of RvD1 proresolution pathway in diabetic GK rats with exogenous RvD1 can prevent SEV-induced cognitive decline by attenuating neuroinflammation in the hippocampus.
Highlights
Post-operative cognitive dysfunction (POCD) is characterized by a decline in cognitive performance following anesthesia and surgery when compared to preoperative cognitive status (Skvarc et al, 2018)
To examine whether resolvin D1 (RvD1) proresolution pathway might be altered in diabetic GK rats in response to SEV exposure, we measured the levels of RvD1 and RvD2 in plasma and CSF and expression of their receptor FPR2 in the hippocampus in GK rats and Wistar rats
The novel findings of the present study are: 1) Type 2 diabetic GK rats, compared with Wistar rats, have lower levels of RvD1 in the periphery and central nervous system (CNS), which are accompanied by decreased expression of its receptor FPR2 in the hippocampus; 2) SEV exposure elevates levels of RvD1 in the periphery and CNS and increases expression of FPR2 in the hippocampus in Wistar rats but not in diabetic GK rats; 3) SEV exposure-induced neuroinflammation in the hippocampus and cognitive decline in diabetic GK rats are prevented by exogenous RvD1, which increases levels of RvD1 in the periphery and CNS and upregulates expression of FPR2 in the hippocampus
Summary
Post-operative cognitive dysfunction (POCD) is characterized by a decline in cognitive performance following anesthesia and surgery when compared to preoperative cognitive status (Skvarc et al, 2018). The precise mechanism underlying POCD remains elusive, preclinical and clinical studies have shown that cognitive impairment can be induced by general anesthetics (Jevtovic-Todorovic et al, 2013; Li et al, 2017; Zhang et al, 2019; Li and Zhang, 2021). Cognitive impairment caused by general anesthetics is dependent on the choice of anesthesia agent, doses of the drug, time or duration of anesthesia administration and patient age (Shen et al, 2013; Callaway et al, 2015). A pre-existing medical condition such as type 2 diabetes mellitus (DM) or chronic intermittent hypoxia may enhance the vulnerability to the development of POCD following anesthesia (Feng et al, 2013; Yang et al, 2014; Yue et al, 2015; Li et al, 2017; Zhang et al, 2019)
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