The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity
The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity
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DOI：
10.1016/j.neuropharm.2019.03.031
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发表时间：
2019-06-01
影响因子：
4.7
通讯作者：
Rammes, Gerhard
中科院分区：
文献类型：
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作者：
Buerge, Martina;Kratzer, Stephan;Rammes, Gerhard
背景：全麻是否会增加阿尔茨海默病(AD)的风险或加速其进展，这是有争议的。阿尔茨海默病发病的一个重要因素是可溶性淀粉样β蛋白(Aβ)寡聚体的积聚，它影响N-甲基-D-天冬氨酸(NMDA)受体的功能，并取消海马长时程增强(LTP)。NMDA受体拮抗剂，在允许生理激活的浓度下，可以防止Aβ诱导的LTP缺陷。麻醉剂氙气和S-氯胺酮都是N-甲基-D-天冬氨酸受体拮抗剂，据报道具有神经保护作用。在这项研究中，我们研究了这些药物的亚麻醉浓度对不同Aβ寡聚体引起的LTP缺陷的影响，并与NMDA亚单位2B(GIuN2B)选择性拮抗剂Radiprodil的作用进行了比较。方法：在小鼠脑片上应用不同的Aβ寡聚体，记录高频刺激前后海马CA1区兴奋性突触后场电位。结果：低浓度氙气和放射性前列地尔可部分恢复预先孵育的Aβ(1)(-42)所致的LTP损伤。S-氯胺酮无作用。所有受试药物均不能改善Aβ(1-)(40)诱导的LTP损伤。结论：亚麻醉浓度的氙气可部分恢复Aβ(1-42)诱导的LTP损伤，其机制可能与其微弱的NMDA受体拮抗作用有关。其作用范围与NMDA-GluN2B拮抗剂Radiprodil相似。我们的结果表明，氙气在病理扭曲的突触生理学背景下具有保护作用，这可能是AD患者麻醉的一种有意义的替代选择。
Background: It is controversially discussed whether general anaesthesia increases the risk of Alzheimer's disease (AD) or accelerates its progression. One important factor in AD pathogenesis is the accumulation of soluble amyloid beta (A beta) oligomers which affect N-methyl-D-aspartate (NMDA) receptor function and abolish hippocampal long-term potentiation (LTP). NMDA receptor antagonists, at concentrations allowing physiological activation, can prevent A beta-induced deficits in LTP. The anaesthetics xenon and S-ketamine both act as NMDA receptor antagonists and have been reported to be neuroprotective. In this study, we investigated the effects of subanaesthetic concentrations of these drugs on LTP deficits induced by different A beta oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GIuN2B)-selective antagonist.Methods: We applied different A beta oligomers to murine brain slices and recorded excitatory postsynaptic field potentials before and after high-frequency stimulation in the CA1 region of hippocampus. Radiprodil, xenon and S-ketamine were added and recordings evoked from a second input were measured.Results: Xenon and radiprodil, applied at low concentrations, partially restored the LTP deficit induced by preincubated A beta(1)(-42). S-ketamine showed no effect. None of the drugs tested were able to ameliorate A beta(1-)(40) -induced LTP-deficits.Conclusions: Xenon administered at subanaesthetic concentrations partially restored A beta(1-42)-induced impairment of LTP, presumably via its weak NMDA receptor antagonism. The effects were in a similar range than those obtained with the NMDA-GluN2B antagonist radiprodil. Our results point to protective properties of xenon in the context of pathological distorted synaptic physiology which might be a meaningful alternative for anaesthesia in AD patients.