Zhou Ran, Bickler Philip
From the *Department of Anesthesia, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; and †Department of Anesthesia and Perioperative Care, University of California San Francisco.
Anesth Analg. 2017 Feb;124(2):582-587. doi: 10.1213/ANE.0000000000001698.
The relationship between inhalational anesthetics such as isoflurane and cognitive impairment in the elderly is controversial. Both β-amyloid peptide (Aβ), associated with Alzheimer disease, and tumor necrosis factor-α (TNF-α), a proinflammatory stress-related peptide, impair the synaptic function. We hypothesized that transient exposure to isoflurane and these peptides would impair synaptic function, manifest as a depression of long-term potentiation (LTP) and paired pulse facilitation (PPF), in the rat hippocampus.
Hippocampal slices were prepared from 3- to 4-week-old male Wistar rats. Preliminary experiments identified minimal concentrations of Aβ1-42 peptide and TNF-α that produced statistically detectable suppressing effects on LTP (600 nM Aβ1-42 and 5 ng/mL TNF-α). These concentrations of peptides were applied to slices alone, with 1.5% isoflurane, or in combination for 1 hour and then washed out. Measurements of LTP (field excitatory postsynaptic potentials [fEPSPs]) from neurons in the CA1 area by stimulation of the Schaffer-Collateral pathway were made after high-frequency stimulation (100 Hz, 1 second). Analysis of variance with correction for multiple comparisons was used to compare LTP under steady-state conditions and averaged for the 40- to 60-minute period after LTP induction.
EPSP amplitude after LTP induction was 155% ± 9% of baseline and was not affected by isoflurane exposure and washout (150% ± 4% of baseline, P = .47). Both Aβ1-42 and TNF-α reduced LTP by approximately 15% compared with control (129% ± 7% and 131% ± 11% of baseline respectively, means ± SD, both P < .001). When Aβ1-42 was combined with isoflurane, LTP was not impaired (151% ± 9% of control, P = .85), but isoflurane had no effect on LTP depression caused by TNF-α or a combination of Aβ and TNF-α.
Brief exposure to isoflurane prevents rather than impairs the decrease in LTP caused by Aβ1-42 in rat hippocampus. In contrast, isoflurane had no effect on synaptic impairment caused by TNF-α or a combination of TNF-α and Aβ. Although this is an in vitro study and translation to clinical medicine requires additional work, the interactions of isoflurane, Aβ, and TNF-α revealed here could have implications for patients with Alzheimer disease or perioperative neuroinflammation.
异氟烷等吸入性麻醉剂与老年人认知功能障碍之间的关系存在争议。与阿尔茨海默病相关的β-淀粉样肽（Aβ）和促炎应激相关肽肿瘤坏死因子-α（TNF-α）均会损害突触功能。我们推测，短暂暴露于异氟烷和这些肽会损害大鼠海马体的突触功能，表现为长时程增强（LTP）和双脉冲易化（PPF）的抑制。
从3至4周龄雄性Wistar大鼠制备海马切片。初步实验确定了对LTP产生统计学可检测抑制作用的Aβ1-42肽和TNF-α的最低浓度（600 nM Aβ1-42和5 ng/mL TNF-α）。将这些肽浓度单独、与1.5%异氟烷一起或联合应用于切片1小时，然后洗脱。在高频刺激（100 Hz，1秒）后，通过刺激Schaffer侧支通路测量CA1区神经元的LTP（场兴奋性突触后电位[fEPSPs]）。采用校正多重比较的方差分析来比较稳态条件下的LTP，并在LTP诱导后40至60分钟期间进行平均。
LTP诱导后的EPSP幅度为基线的155%±9%，不受异氟烷暴露和洗脱的影响（为基线的150%±4%，P = 0.47）。与对照组相比，Aβ1-42和TNF-α均使LTP降低约15%（分别为基线的129%±7%和131%±11%，均值±标准差，P均<0.001）。当Aβ1-42与异氟烷联合使用时，LTP未受损（为对照组的151%±9%，P = 0.85），但异氟烷对TNF-α或Aβ与TNF-α联合引起的LTP抑制无影响。
短暂暴露于异氟烷可预防而非损害大鼠海马体中由Aβ1-42引起的LTP降低。相比之下，异氟烷对TNF-α或TNF-α与Aβ联合引起的突触损伤无影响。尽管这是一项体外研究，向临床医学的转化还需要更多工作，但此处揭示的异氟烷、Aβ和TNF-α之间的相互作用可能对阿尔茨海默病患者或围手术期神经炎症患者有影响。
