Inhibition of astrocytic toll-like receptor 4 contributes to sevoflurane pretreatment-induced anti-neuroinflammation following focal cerebral ischemia

Background

Sevoflurane, a widely used clinical anesthetic, exhibits neuroproctive properties though its precise mechanisms remain unclear. Astrocytes, a critical regulators of immune responses, actively participate in sevoflurane-mediated neuroprotection against ischemia. Toll-like receptor 4 (TLR4), a key molecule for conversion from pro-inflammatory astrocytes to anti-inflammatory astrocytes phenotypes. The present study explores the role of astrocytic TLR4 in sevoflurane preconditioning mediated neuroprotection after focal cerebral ischemia.

Methods

In vivo, mice were preconditioned with 2.0 % sevoflurane before right middle cerebral artery occlusion/reperfusion (MCAO/R). In vitro, primary astrocytes were pretreated with sevoflurane and followed by 4 h oxygen-glucose deprivation for astrocytes and 2 h for astrocyte-neuron cocultures. Astrocytic TLR4 expression and its role in sevoflurane preconditioning in cerebral ischemia were assessed using western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Results

The expression of TLR4 and the levels of inflammatory cytokines both within the penumbra and in primary astrocytes significantly increased following ischemia, further exacerbating neural damage. In vivo, sevoflurane preconditioning reduced the expression of TLR4 as well as the levels of TNFα and IL-6. Consistently, it improved neurological deficit scores and decreased infarct volume. In vitro, sevoflurane preconditioning prevented the increasing of TLR4 as well as the levels of TNFα and IL-6 of primary astrocytes and decreased the over-expression of cleaved-caspase 3 and primary neuron apoptosis in astrocyte-neuron co-cultures.

Conclusions

Our findings demonstrate that sevoflurane preconditioning attenuates ischemia-mediated neuroinflammation by suppressing astrocytic TLR4 expression, highlighting its therapeutic potential against neuroinflammation induced by focal cerebral ischemia.