中图分类号:
R971.2;R965
文献标识码:
A
文章编号:
1004-0781(2019)03-0309-04
摘要:
目的 观察脂氧素A4 (LXA4)对异氟烷麻醉诱发老龄大鼠促炎因子释放及认知功能障碍的影响。方法 将120只雄性SD大鼠随机分成对照组(C组)、异氟烷组(I组)、LXA4+异氟烷组(L+I组)和LXA4组(L组)(n=30)。异氟烷麻醉开始前,L组和 L+I 组脑室注射0.3 nmol·L-1 LXA4 5 μL,C组和I组脑室注射等量0.9%氯化钠溶液。C组和L组大鼠以30%O2-70%N2混合气体处理6 h,I组和L+I组大鼠以1.4%异氟烷处理6 h。麻醉结束后测定动脉血气及血糖,麻醉后0,3,6,12和24 h监测海马肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)、白细胞介素1β(IL-1β)和核因子κB抑制因子α(IκBα)表达,每次5只。其余大鼠完全清醒后,饲养至麻醉后2周,Morris水迷宫实验检测空间学习和记忆能力,分离海马,Western Blotting检测IκBα表达水平。结果 与C 组比较,I组麻醉后0,3,6 h IL-1β和 IL-6表达明显上调(P<0.05);麻醉后0,3,6,12 h TNF-α表达明显上调(P<0.05);麻醉后0,3,6 h IκBα表达下调(P<0.05)。与I组比较,L+I组麻醉后0,3,6 h TNF-α、IL-1β和 IL-6表达下调,IκBα表达上调(P<0.05)。水迷宫实验训练第3天和第4天,与I组比较,L+I组大鼠定位平台时间缩短,在目标象限的时间百分比更高(P<0.05)。结论 LXA4可改善异氟烷麻醉所致的老年大鼠学习记忆功能障碍,其机制可能与抑制老年大鼠海马促炎因子释放有关。
关键词:
脂氧素A4
;
异氟烷
;
认知障碍
;
炎症因子
Abstract:
Objective To investigate the effect of lipoxin A4 on aged rats with isoflurane-induced neuroinflammation and cognitive dysfunction in aged rats. Methods One hundred and twenty male SD rats, were randomly assigned into 4 groups (n=30): control group (group C), 1.4% isoflurane group (group I), 0.3 nmol·L-1 Lipoxin A4+1.4% isoflurane group (group L+I) and 0.3 nmol·L-1 Lipoxin A4 group (group L).Lipoxin A4 was administered by intracerebroventricular injection before the start of anesthesia in group L+I and group L, respectively.Group I and group L+I was exposed to 1.4% isoflurane for 6 h, while group C and group L exposed to 30%O2-70%N2.At the end of anesthesia, 25 rats in each group were randomized to do arterial blood gas test and expression of TNF-α, IL-6, IL-1β and IκBα (0, 3, 6, 12 and 24 h after anesthesia) was detected.The other rats in each group were sent back to their home cage until they were fully awake.Fourteen days after anesthesia, Morris water maze was used to assess the cognitive function; and then hippocampus of rats was dissected for detection of the expression of IκBα. Results As compared with group C, IL-6 and IL-1β were significantly increased 0, 3 and 6 h after anesthesia, TNF-α was significantly increased 0, 3, 6 and 12 h after anesthesia, IκBα was significantly decreased 0, 3 and 6 h after anesthesia in group I (P<0.05).As compared with group I, TNF-α, IL-1β and IL-6 were significantly decreased and IκBα significantly increased 0, 3 and 6 h after anesthesia in group L+I (P<0.05).On the 3rd and 4th day of Morris water maze test, rats in the group L+I spent less time locating the platform than those in group I, and the percentage of time spent in the target quadrant was more in the group L+I than in group I (P<0.05). Conclusion Lipoxin A4 can attenuate cognitive dysfunction induced by isoflurane in aged rats.The mechanism is associated with inhibition of hippocampal proinflammatory cytokines which is increased by isoflurane.
Fig.1
Latency to arriving to platform (A) and time percentage in target quadrant (B) of four groups of rats($\bar{x}$±s,n=5) Compared with group C,*1P<0.05; Compared with group I,*2P<0.05
Fig.2
Effect of LXA4 on the expression of TNF-α, IL-1β, IL-6 and IκBα in hippocampus of rats($\bar{x}$±s,n=5) A-C.expression of TNF-α、IL-1β and IL-6 in hippocampus of rats; D.IκBα expression in hippocampus of rats;Compared with group C,*1P<0.05; Compared with group I,*2P<0.05
研究表明,在神经退行性疾病中,TNF-α和 IL-1β参与了海马内神经炎症反应,而阻止TNF-α和 IL-1β释放可以改善认知功能[10]。笔者在本研究发现,与C组比较,I组麻醉后0,3,6 h TNF-α、IL-1β和 IL-6表达明显上调;麻醉后0,3,6 hIκBα表达下调,第3~4天逃避潜伏期延长,探索时间缩短。提示1.4%异氟烷可诱导海马内TNF-α、IL-1β和IL-6释放,可能参与诱导神经炎症的发生和发展,从而导致老年大鼠发生认知功能障碍。
LXA4是花生四烯酸的代谢产物,在炎症等病理过程中具有抗炎和促炎症消退作用[11]。在诸多神经系统疾病中,LXA4可以通过抑制胶质细胞激活、降低炎症因子(TNF-α、IL-1β)活性等发挥神经保护作用[12]。研究发现,与I组比较,L+I组在麻醉结束后0,3,6 h TNF-α、IL-1β和 IL-6表达下调,IκBα表达上调,LXA4预处理可抑制异氟烷诱导的炎症因子的增加;L组和L+I组各时间点TNF-α、IL-1β及IL-6表达差异无统计学意义;麻醉结束后24 h,各组TNF-α、IL-1β及IL-6差异无统计学意义。与I组比较,L+I组第3~4天逃避潜伏期缩短,探索时间延长,提示LXA4预处理可减轻异氟烷诱发的神经炎症反应,改善异氟烷麻醉诱发的老龄大鼠认知功能障碍。
LXA4能抑制炎性刺激引起的多种细胞因子、趋化因子、黏附分子表达,其机制与抑制NF-κB活性相关[11],而IκBα降解是NF-κB释放的中心环节[13]。LXA4抑制TNF-α、IL-1β和 IL-6增加,其机制可能是抑制IκBα蛋白降解,通过衰减IκBα降解抑制NF-κB转录活性,从而抑制炎症因子TNF-α、IL-1β和 IL-6等的释放,减轻神经炎症反应,改善认知功能。笔者在本研究中发现,与C 组比较,I组麻醉后0,3,6 h IκBα表达下调,12 h后恢复正常;与I组比较,L+I组IκBα表
STEINMETZJ,CHRISTENSEN KB,LUNDT,et al.Long-term consequences of postoperative cognitive dysfunction[J].Anesthesiology,2009,110(3):548-555.
Postoperative cognitive dysfunction (POCD) is common in elderly patients after noncardiac surgery, but the consequences are unknown. The authors' aim was to determine the effects of POCD on long-term prognosis. This was an observational study of Danish patients enrolled in two multicenter studies of POCD between November 1994 and October 2000. The cohort was followed up from the date of surgery until August 2007. Cognitive function was assessed by a neuropsychological test battery at three time points: before, at 1 week after, and at 3 months after noncardiac surgery. Data on survival, labor market attachment, and social transfer payments were obtained from administrative databases. The Cox proportional hazards regression model was used to compute relative risk estimates for mortality and disability, and the relative prevalence of time on social transfer payments was assessed by Poisson regression. A total of 701 patients were followed up for a median of 8.5 yr (interquartile range, 5.3-11.4 yr). POCD at 3 months, but not at 1 week, was associated with increased mortality (hazard ratio, 1.63 [95% confidence interval, 1.11-2.38]; P = 0.01, adjusted for sex, age, and cancer). The risk of leaving the labor market prematurely because of disability or voluntary early retirement was higher among patients with 1-week POCD (hazard ratio, 2.26 [1.24-4.12]; P = 0.01). Patients with POCD at 1 week received social transfer payments for a longer proportion of observation time (prevalence ratio, 1.45 [1.03-2.04]; P = 0.03). Cognitive dysfunction after noncardiac surgery was associated with increased mortality, risk of leaving the labor market prematurely, and dependency on social transfer payments.
Anesthetics have been reported to promote Alzheimer's disease (AD) neuropathogenesis by inducing β-amyloid protein accumulation and apoptosis. Neuroinflammation is associated with the emergence of AD. We therefore set out to determine the effects of the common anesthetic isoflurane on the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, the proinflammatory cytokines, in vitro and in vivo, employing Western blot, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and reverse transcriptase polymerase chain reaction (RT-PCR). Here, we show that a clinically relevant isoflurane anesthesia increased the protein and messenger ribonucleic acid (mRNA) levels of TNF-α, IL-6, and IL-1β in the brain tissues of mice. The isoflurane anesthesia increased the amounts of TNF-α immunostaining positive cells in the brain tissues of mice, the majority of which were neurons. Furthermore, isoflurane increased TNF-α levels in primary neurons, but not microglia cells, of mice. Finally, isoflurane induced a greater degree of TNF-α increase in the AD transgenic mice than in the wild-type mice. These results suggest that isoflurane may increase the levels of proinflammatory cytokines, which may cause neuroinflammation, leading to promotion of AD neuropathogenesis.
WUL,LIU ZJ,MIAOS,et al.Lipoxin A4 ameliorates cerebral ischaemia/reperfusion injury through upregulation of nuclear factor erythroid 2-related factor 2[J].Neurol Res,2013,35(9):968-975.
Objectives: Lipoxin A4 (LXA4) is a potent anti-inflammatory mediator that exerts a neuroprotective effect following cerebral ischaemia/reperfusion (I/R) injury. However, little is known about the underlying mechanisms. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is generally considered to reduce cerebral I/R injury. Nuclear factor erythroid 2-related factor 2 can induce haeme oxygenase-1 (HO-1) and glutathione (GSH) expression to combat increased oxidative stress. The present study aimed to investigate the effects of Nrf2 signalling on LXA4-mediated neuroprotection.
SUD,ZHAOY,WANGB,et al.Isoflurane-induced spatial memory impairment in mice is prevented by the acetylcholinesterase inhibitor donepezil[J].PLoS One,2011,6(11):e27632.
Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and 7 nicotinic receptor (7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or 7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.
Cognitive decline following surgery in older individuals is a major clinical problem of uncertain mechanism; a similar cognitive decline also follows severe infection, chemotherapy, or trauma and is currently without effective therapy. A variety of mechanisms have been proposed, and exploring the role of inflammation, we recently reported the role of IL-1β in the hippocampus after surgery in mice with postoperative cognitive dysfunction. Here, we show that TNF-α is upstream of IL-1 and provokes its production in the brain. Peripheral blockade of TNF-α is able to limit the release of IL-1 and prevent neuroinflammation and cognitive decline in a mouse model of surgery-induced cognitive decline. TNF-α appears to synergize with MyD88, the IL-1/TLR superfamily common signaling pathway, to sustain postoperative cognitive decline. Taken together, our results suggest a unique therapeutic potential for preemptive treatment with anti-TNF antibody to prevent surgery-induced cognitive decline.
61Effects of aspirin-triggered-lipoxin A4 (ATL) on astrocytes inflammatory response were evaluated.61Inflammatory response was induced by lipopolysaccharide in cultured cortical astrocytes.61ATL inhibited production of nitric oxide and prostaglandin E2.61ATL reduced the expression of cyclooxygenase 2 and inducible nitric oxide synthase.61ATL attenuated NF-κB signal transducer pathway.
WUJ,WANGA,MINZ,et al.Lipoxin A4 inhibits the production of proinflammatory cytokines induced by β-amyloid in vitro and in vivo[J].Biochem Biophys Res Commun,2011,408(3):382-387.
Studies increasingly indicate that inflammation induced by β-amyloid (Aβ) contributes to the progression of Alzheimer’s disease (AD). How to inhibit the enhanced production of proinflammatory cytokines stimulated by Aβ is an important research subject for the treatment of AD. In this study, we investigated the inhibitory effect and the molecular mechanism of the lipoxin A4 (LXA4) on the production of interleukin-1β (IL-1β) and tumor necrosis factorα (TNFα) induced by β-amyloid in the cortex and hippocampus of mice, and in Aβ-stimulated BV2 cells, a mouse microglial cell line. LXA4 down-regulated the protein expression of IL-1β and TNFα, attenuated the gene expressions of IL-1β and TNFα, inhibited the degradation of IκBα, inhibited translocation of NF-κB p65 subunit into the nucleus induced by β-amyloid in the cortex and hippocampus of mice, and in Aβ-stimulated BV2 cells, and the inhibitory effects were dose dependently elevated. Our findings suggest that LXA4 inhibits the production of IL-1β and TNFα induced by β-amyloid in the cortex and hippocampus of mice, and in BV2 microglial cells via the NF-κB signal pathway.
, 李世勇
