The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory.
The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory.
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DOI：
10.1016/j.neuroscience.2011.09.006
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发表时间：
2011-12-01
期刊：
影响因子：
3.3
通讯作者：
Prast, H.
中科院分区：
文献类型：
--
作者：
Hornick, A.;Lieb, A.;Vo, N. P.;Rollinger, J. M.;Stuppner, H.;Prast, H.
关键词：
在以前的研究中，简单的，天然衍生的香豆素东莨菪碱（SCT）被确定为乙酰胆碱酯酶（AChE）的抑制剂，使用基于药效团的虚拟筛选方法。在这项研究中，SCT作为前胆碱能和认知增强治疗的潜力进行了更详细的研究，使用不同的实验方法，如测量新合成的乙酰胆碱（ACh）在突触体，长时程增强（LTP）实验在海马切片，和行为研究。SCT可增强K+刺激的大鼠额叶皮层突触体ACh释放，呈钟形量效曲线（Emax：4 μM）。这种作用可被烟碱乙酰胆碱受体（nAChR）拮抗剂美加明（MEC）和二氢-β-赤藓定（DHE）阻断。nAChR激动剂（和AChE抑制剂）加兰他敏诱导了类似的ACh释放增加（Emax：1 μM）。SCT增强大鼠海马脑片LTP。在高频刺激（HFS）前应用SCT（4 μM，4 min）可显著增强HFS诱导的、N-甲基-D-天冬氨酸（NMDA）受体依赖的CA 3-CA 1突触场兴奋性突触后电位的LTP。尼古丁（2 μM）模拟了这种作用，MEC消除了这种作用，表明对nAChR有影响。SCT不能完全恢复NMDA受体拮抗剂d，l-2-氨基-5-膦酰基戊酸（AP-5）对LTP的抑制作用。SCT（2 μg，i.c.v.）增加东莨菪碱诱导的胆碱能缺陷小鼠的T-迷宫交替和改善新物体识别。它还减少了15-18个月大的小鼠与年龄相关的物体记忆缺陷（皮下注射2毫克/千克）。我们的研究结果表明，SCT具有记忆改善的属性，这是基于其直接nAChR激动活性。因此，SCT可能能够通过增强nAChR介导的神经递质释放和促进海马神经可塑性来挽救受损的胆碱能功能。香豆素东莨菪碱被描述为AChE抑制剂。现在，我们表明它通过nAChRs发挥有前途的前认知特性。③增强ACh的释放，增强海马LTP。它改善东莨菪碱遗忘小鼠的新物体识别和T-迷宫交替，并改善年龄受损小鼠的物体记忆。
In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (Emax: 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (Emax: 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15–18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus. ▶The coumarin scopoletin has been described as AChE inhibitor. ▶Now we show it exerts promising procognitive properties via nAChRs. ▶It enhances release of ACh and potentiates hippocampal LTP. ▶It improves novel object recognition and T-maze alternation in scopolamine-amnestic mice and ameliorates object memory in age-impaired mice.
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