In the present study, treatment with propofol was associated with reduced pro-inflammatory cytokine expressions at 24 hours after ischemic brain injury, the peak timepoint of those mRNA expression levels16 and attenuates ischemic brain injury, suggesting that propofol exerts neuroprotective effects via its anti-inflammatory capacity. Because propofol at the dose used did not affect the hemodynamic parameters investigated, the effects of propofol on cardiovascular function were not likely to be involved in the neuroprotection observed in the present study.
The immune system is promptly activated once ischemic brain injury occurs.16 Among various inflammatory mediators, TLR is considered crucial in innate immune system as a first-line defense and mediator of inflammation.17, 18 Exogenous/endogenous TLR ligands such as heat shock proteins, fibrinogen, and components of the extracellular matrix are upregulated by ischemic brain insult. Consequently, those ligands then activate TLR4,19, 20 the TLR shown to be the pivotal inflammatory mediator in the pathogenesis of ischemic brain injury.11, 12 It has been reported that while activation of TLR4 exacerbates cerebral infarction,11 inhibition of the receptor suppresses pro-inflammatory responses and attenuates brain injury.12
In the current study, the neuroprotective effect of propofol against ischemic brain injury was abrogated by depletion of TLR4, indicating that the TLR4-dependent pathway was substantially involved in the mechanism underlying that neuroprotective effect. The results of the current study are concordant with recent in vivo studies in which propofol suppressed inflammatory cytokine production via inhibition of TLR4-dependent pathways in various disease models, including lung,8 liver,9 and gastric injuries10 and asthma.21 Several in vitro studies using lipopolysaccharide-treated microglia,22 macrophages,23 spinal astrocytes,24 and alveolar epithelial cells25 also suggest that the anti-inflammatory action of propofol involves blocking the TLR4-dependent pathway and consequent pro-inflammatory cytokine production.
Our result showed significantly lower IL-6 mRNA expression levels in the brains of propofol-treated wild-type mice than in the brains of control mice, which is consistent with an earlier study in which there was a correlation between infarct volume and IL-6 mRNA expression in the brain.26 Among various pro-inflammatory cytokines, IL-6 plays pivotal roles in local inflammation and cytotoxicity after ischemic brain injury, and is involved in the mechanism underlying the expansion of ischemic brain injury.27, 28 Blockade of IL-6 receptors has been shown to reduce infarct volume and improve cognitive function in an experimental model of ischemic stroke.29 These earlier studies are concordant with the suppression of IL-6 by propofol observed in the current study after ischemic brain insult, as well as the reduction of infarct volume.
Based on the collective results of the previous studies and the current study, it is reasonable to surmise that propofol exerts neuroprotection against ischemic brain injury by blocking TLR4 and suppressing consequent production of pro-inflammatory cytokines, particularly IL-6. The clinical importance of the present study is that the results indicates that bolus propofol administration prior to ischemic insult can protect against ischemic brain injury, presumably by blocking the TLR4-dependent pathway. This understanding of the mechanism underlying the neuroprotective effect of propofol against ischemic brain injury may lead to a novel strategy to prevent exacerbation of ischemic brain injury.
With regards to study limitations, only relatively young male mice were used. Further studies should test aged mice and female mice at different menopausal stages, because those biological variables can affect the outcomes of ischemic brain injury.