Perioperative neurocognitive disorders have been widely recognized as common adverse events after surgical intervention. Aging is one of the most important independent risk factors for worsened cognitive outcome, and this deterioration is linked to exacerbated microglia‐mediated neuroinflammation in the aged brain. Under pathological stimulation, microglia are capable of polarizing toward proinflammatory M1 and anti‐inflammatory M2 phenotypes. In the present study, we examined how aging affects microglial responses and neuroinflammation following peripheral surgery. Adult (2‐3 months) and aged (18 months old) male C57/BL6 mice were subjected to tibial fracture or sham surgery. Aged mice exhibited higher level of tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) in the hippocampus. The expression of synaptic protein synaptophysin (SYP) was also markedly reduced in the aged brain after the surgery. Both adult and aged mice showed significant increases in M1 microglial polarization (CD16/32). In contrast, tibial fracture surgery induced a decreased M2 microglial polarization (CD206, Ym1/2, Arg1) in aged brain but enhanced M2 microglial polarization in adult brain. Aged mice have upregulated voltage‐gated proton channel (Hv1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression compared with adult mice. The percentage of CD16/32‐positive M1 microglia colabeling with Hv1 was higher in aged mice after tibial fracture surgery. Thus, Hv1/NADPH oxidase upregulation in the aged brain may shift the dynamic equilibrium of microglial activation toward M1 polarization and exaggerate postoperative neuroinflammatory responses after peripheral surgical intervention.

No abstract

No abstract

Propofol is a short-acting intravenous anesthetic agent with potential neuroprotective effect. In this study, we aim to investigate whether delayed propofol treatment is protective against lipopolysaccharide (LPS)-stimulated inflammatory responses in microglial cells. Cultured BV2 microglial cells were exposed to propofol at various time points after initiation of LPS stimulation. Nitrite production and cell viability were assessed after stimulation with LPS for 24 h. The effect of propofol on mRNA levels of cyclooxygenase-2 (Cox-2), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) was analyzed using reverse transcription PCR (RT-PCR) 6 h after LPS stimulation. The production of TNF-α and reactive oxygen species was also studied. Propofol applied 0–4 h after the initiation of LPS dose-dependently inhibits nitric oxide production. Propofol application also decreased LPS-induced Cox-2, IL-6, iNOS, TNF-α, and IL-1β mRNA expression and induced significant protein kinase B (PKB) phosphorylation in BV2 cells. Treatment with phosphoinositide 3-kinase (PI3K)/PKB inhibitor wortmannin decreased PKB phosphorylation induced by propofol, and abolished the inhibitory effect of propofol on LPS-stimulated NO, reactive oxygen species and TNF-α production. Our results suggest that delayed propofol treatment can reduce LPS-induced activation of microglial cells. These effects may be mediated by activation of the PI3K/PKB pathway.