Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activation of the PI3K/Akt/mTOR pathway

Nan Wang,Mingyu Wang

doi:10.1186/s12871-019-0808-5

Abstract

BackgroundSevoflurane, an inhalational general anesthetic, has become one of the most widely used inhalational anesthetics in surgery. However, previous studies have found that sevoflurane anesthesia can trigger an inflammatory response, resulting in secondary damage. Dexmedetomidine (DEX), a highly-selective α adrenergic receptor agonist, is widely used as an anesthetic adjuvant in the clinic. In this study we investigated whether DEX was able to suppress sevoflurane-induced neuroinflammation.MethodsThe aim was to determine the mechanism of action of the suppressive effect of DEX using a rat model. Rats were randomly divided into a control group (n = 10), low-dose sevoflurane group (L-Sev; n = 10), high-dose sevoflurane group (H-Sev; n = 10), vehicle group (n = 10), DEX group (n = 10) and DEX + LY294002 (a specific inhibitor of PI3K) group (n = 10). The rats in vehicle, DEX and DEX + LY294002 groups were in the presence of high-dose sevoflurane exposure. Western blotting was used to measure the expression of proinflammatory cytokines (IL-6, IL-8, TNF-α) and the activity level of the phosphatidylinositol 3-hydroxy kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.ResultsWe found that sevoflurane anesthesia induced an increase in the levels of pro-inflammatory cytokines, while decreasing activation of the PI3K/Akt/mTOR pathway in both the cortex and hippocampus of rats. Treatment with DEX reduced pro-inflammatory cytokine levels and prevented inactivation of the PI3K/Akt/mTOR pathway. Moreover, LY294002, an inhibitor of the PI3K/Akt/mTOR pathway, reduced the anti-inflammatory activity of DEX.ConclusionsThese data suggest that the PI3K/Akt/mTOR pathway contributes to sevoflurane-induced neuroinflammation and that activation of PI3K/Akt/mTOR signaling by DEX could help reduce the neuroinflammatory effects of sevoflurane.

Highlights

Sevoflurane, an inhalational general anesthetic, has become one of the most widely used inhalational anesthetics in surgery
Given the inflammation induced by sevoflurane and the anti-inflammatory properties of DEX, we aimed to ascertain whether DEX could provide protection from sevoflurane anesthesia-induced inflammation in the central nervous system (CNS) and ascertain whether these protective effects were closely associated with the phosphatidylinositol 3-hydroxy kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway
Sevoflurane induced neuroinflammation in rats To determine the effect of sevoflurane on neuroinflammation, expression levels of the inflammatory markers IL-6, IL-8 and TNF-α were measured in the cortex and hippocampus of rats in the control, low-dose sevoflurane group (L-Sev) and high-dose sevoflurane group (H-Sev) groups by Western blotting

Summary

Introduction

Sevoflurane, an inhalational general anesthetic, has become one of the most widely used inhalational anesthetics in surgery. Wang et al found that treatment with DEX could inhibit the expression of inflammatory cytokines and their mediators, resulting in reduced focal cerebral ischemia-reperfusion injury in rats. These data suggest that inhibition of the nuclear factor-κB pathway (NF-κB) may be a mechanism underlying the neuroprotective action of DEX [14]. DEX has been shown to improve post-operative cognitive dysfunction in aging mice by inhibition of the hippocampal inflammatory response and reduction of neuronal apoptosis [16] Taken together, these data suggest that DEX has anti-inflammatory properties in the central nervous system (CNS)

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