Isoflurane anesthesia in aged mice and effects of A1 adenosine receptors on cognitive impairment.

AIMS: Isoflurane may not only accelerate the process of Alzheimer's disease (AD), but increase the risk of incidence of postoperative cognitive dysfunction (POCD). However, the underlying mechanisms remain unknown. This study was designed to investigate whether isoflurane contributed to the POCD occurrence through A1 adenosine receptor (A1AR) in aged mice. METHODS: We assessed cognitive function of mice with Morris water maze (MWM) and then measured expression level of two AD biomarkers (P-tau and Aß) and a subtype of the NMDA receptor (NR2B) in aged wild-type (WT) and homozygous A1 adenosine receptor (A1AR) knockout (KO) mice at baseline and after they were exposed to isoflurane (1.4% for 2 hours). RESULTS: For cognitive test, WT mice with isoflurane exposure performed worse than the WT mice without isoflurane exposure. However, A1AR KO mice with isoflurane exposure performed better than WT mice with isoflurane exposure. WT mice exposed to isoflurane had increased levels of Aß and phosphorylated tau (P-tau). Levels of Aß and P-tau were decreased in A1AR KO mice, whereas no differences were noted between KO mice with and without isoflurane exposure. NR2B expression was inversely related to that of P-tau, with no differences found between KO mice with and without isoflurane exposure. CONCLUSIONS: We found an association between isoflurane exposure, impairment of spatial memory, decreasing level of NR2B, and increasing levels of A-beta and P-tau, presumably via the activation of the A1A receptor.

IFN-gamma down-regulates ABCA1 expression by inhibiting LXRalpha in a JAK/STAT signaling pathway-dependent manner.

Interferon gamma (IFN-gamma) is an immunomodulatory and anti-microbial cytokine, which has a variety of proatherogenic effects. It has been reported that IFN-gamma can down-regulate ABCA1 expression. However, its mechanism is elusive. In the present study, we have investigated the effect of IFN-gamma on ABCA1 expression and cholesterol efflux in THP-1 macrophage-derived foam cells. IFN-gamma decreased ABCA1 expression at both transcriptional and translational levels in a dose-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by IFN-gamma treatment. Liver X receptor alpha (LXRalpha), which can regulate the expression of ABCA1, was also down-regulated by IFN-gamma treatment. LXRalpha-specific activation by LXRalpha agonist almost compensated the down-regulation of ABCA1 expression by IFN-gamma, while siRNA of LXRalpha led to down-regulation of ABCA1 expression more significantly than IFN-gamma. IFN-gamma induced phosphorylation of STAT1 and expression of STAT1alpha in the nucleus, which was inhibited by a JAK inhibitor AG-490. Treatment with STAT1 siRNA further enhanced down-regulation of LXRalpha mRNA by IFN-gamma. Furthermore, AG-490 and STAT1 siRNA almost compensated the effect of IFN-gamma on ABCA1 expression and cholesterol efflux. In conclusion, IFN-gamma may first down-regulate expression of LXRalpha through the JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study may be useful in understanding the critical effect of IFN-gamma in pathogenesis of atherosclerosis.

The effect of T0901317 on ATP-binding cassette transporter A1 and Niemann-Pick type C1 in apoE-/- mice.

Although a range of studies indicated Liver X receptor (LXR) activation inhibited the development of atherosclerosis in animal models, the mechanism of this effect for LXR agonists has not been fully understood. A recent study has suggested LXR activators increased the amount of free cholesterol in the plasma membrane of human macrophages by inducing Niemann-Pick type C1 (NPC1) gene expression. Therefore, we hypothesize that LXRs may also promote NPC1 expression in vivo. Here we investigated the effect of a synthetic LXR agonist T0901317 on ATP-binding cassette transporter A1 (ABCA1) and NPC1 in apolipoprotein E knockout (apoE-/-) mice. Male apoE-/- mice were randomized into four groups: baseline group (n = 10), vehicle group (n = 14), prevention group (n = 14), and treatment group (n = 14). En face analysis and Oil red O staining were used to examine the aortic atherosclerotic lesions. Macrophage content of aortic root atherosclerotic lesions and cholesterol efflux form peritoneal macrophages were measured. Gene and protein expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting, respectively. T0901317 treatment reduced aortic atherosclerotic lesion area by 64.2% in prevention group (P < 0.001) and 58.3% in treatment group (P < 0.001) and resulted in a reduction in macrophage content. Plasma triglyceride, total cholesterol, high-density lipoprotein cholesterol, and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 also promoted ABCA1 and NPC1 gene and protein levels in the aorta, liver, and small intestine of apoE-/- mice and significantly increased cholesterol efflux from peritoneal macrophages. T0901317 upregulates ABCA1 and NPC1. This study gives us a new insight into the mechanism for antiatherogenic effect of LXR synthetic agonists.