Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.
Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain.
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DOI：
10.1016/j.brainres.2011.11.004
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发表时间：
2012-01-11
期刊：
影响因子：
2.9
通讯作者：
Bramlett HM
中科院分区：
文献类型：
--
作者：
Mawhinney LJ;de Rivero Vaccari JP;Alonso OF;Jimenez CA;Furones C;Moreno WJ;Lewis MC;Dietrich WD;Bramlett HM
术后认知功能障碍，POCD，困扰着大量的老年手术患者术后全身麻醉。POCD的发病机制尚不清楚。N-甲基-D-天冬氨酸（NMDA）受体，在学习和记忆中至关重要，显示蛋白质表达随年龄的变化是由吸入麻醉剂调节。本研究的目的是确定蛋白质表达的变化，在NMDA受体亚基和下游信号通路的老年大鼠表现出麻醉诱导的空间学习障碍。将3月龄和18月龄雄性Fischer 344大鼠随机分配至接受1.8%异氟烷/70%一氧化二氮（N2 O）麻醉4小时或不麻醉。在麻醉后2周和3个月，在Morris水迷宫中评估空间学习能力。对18月龄大鼠的海马和皮质蛋白裂解物进行免疫印迹，以检测活化的半胱天冬酶3、NMDA受体亚单位和细胞外信号调节激酶（ERK）1/2。在一项单独的实验中，在麻醉前通过腹腔注射给予18月龄大鼠Ro 25-6981（0.5 mg/kg剂量）。在海马蛋白裂解物上进行NR 2B的免疫印迹。在麻醉后3个月，在18个月大时接受麻醉治疗的大鼠表现出空间学习障碍，对应于海马和皮质中NR 2B蛋白表达的急性和长期增加以及磷酸化ERK 1/2的减少。Ro 25-6981预处理减弱了急性NR 2B蛋白表达的增加。我们的研究结果表明，NMDA受体介导的信号通路在海马和皮质的异氟烷/N2 O麻醉处理的大鼠在18个月大的破坏的作用，导致这些动物的空间学习缺陷。一个潜在的治疗干预麻醉相关的认知功能障碍进行了讨论。
Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70 % nitrous oxide (N2O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2 weeks and 3 months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3 months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N2O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.
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