BackgroundGlial cells, including microglia and astrocytes, are considered the primary source of proinflammatory cytokines in the brain. Immune insults stimulate glial cells to secrete proinflammatory cytokines that modulate the acute systemic response, which includes fever, behavioral changes, and hypothalamic-pituitary-adrenal (HPA) axis activation. We investigated the effect of general anesthetics on proinflammatory cytokine expression in the primary cultured glial cells, the microglial cell line BV-2, the astrocytic cell line A-1 and mouse brain. Methodology/Principal FindingsPrimary cultured glial cells were exposed to lipopolysaccharide (LPS) in combination with general anesthetics including isoflurane, pentobarbital, midazolam, ketamine, and propofol. Following this treatment, we examined glial cell expression of the proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). LPS-induced expression of IL-1β mRNA and protein were significantly reduced by all the anesthetics tested, whereas IL-6 and TNF-α mRNA expression was unaffected. The anesthetics suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation, but did not affect nuclear factor-kappaB and activator protein-1 activation. The same effect was observed with BV-2, but not with A-1 cells. In the mouse experiments, LPS was injected intraperitoneally, and isoflurane suppressed IL-1β in the brain and adrenocorticotropic hormone in plasma, but not IL-1β in plasma.Conclusions/SignificanceTaken together, our results indicate that general anesthetics inhibit LPS-induced IL-1β upregulation in glial cells, particularly microglia, and affects HPA axis participation in the stress response.
State of shock, deteriorated consciousness level, chronic obstructive lung disease, ischemic heart disease, hemorrhage requiring blood transfusion, age over 80 years, cardiovascular surgery, surgeries at night, and surgeries of duration more than 2 h cause patients to be strongly susceptible to postoperative mortality or morbidity in emergency surgeries.
Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells.
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