Lili Veronika Nagy, Zsolt Kristóf Bali, István Ledneczki, Zsolt Némethy, Balázs Lendvai, István Hernádi
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Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. 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引用次数: 0
摘要
针对烟碱乙酰胆碱受体(nAChR)或N-甲基-D-天冬氨酸受体(NMDAR)的新药理学策略在提高认知能力方面大有可为。此外,人们对联合靶向上述神经递质系统的低剂量联合疗法也越来越感兴趣,以达到比单一疗法更高的疗效,并减少高剂量单一疗法可能产生的副作用。在本研究中,我们评估了α7 nAChR选择性激动剂PHA-543613(PHA)、新型α7 nAChR正异位调节剂化合物(CompoundX)和NMDAR拮抗剂美金刚对大鼠海马CA1锥体神经元体内发射活动的调节作用。实验采用了三种不同的测试条件:自发发射活动、NMDA诱发发射活动和ACh诱发发射活动。结果显示,高剂量而非低剂量的美金刚能降低NMDA诱发的发射活动,而低剂量的美金刚能提高自发发射活动和ACh诱发的发射活动。全身应用 PHA 可显著增强 ACh 诱导的发射活动,而对 NMDA 诱导的活动没有影响。此外,CompoundX 还能增强 NMDA 和 ACh 诱发的发射活动,但对神经元的自发发射没有影响。在所有测试条件下,低剂量美金刚和 PHA 的组合都能增加发射活动,美金刚和 CompoundX 也有类似的效果,但没有增加自发发射活动的效果。我们目前的研究结果表明,α7 nAChR 药物能与阿尔茨海默病药物美金刚产生有益的相互作用。此外,正性异位调节剂能在正确的时间和正确的地点增强美金刚的作用,而不会影响自发发射活动。所有这些数据都证实了之前的行为学证据,证明了联合疗法在增强认知能力方面的可行性。
Cellular Mechanisms of Cognitive Enhancement: The In Vivo Modulation of the Firing Activity and the Responsiveness of Rat Hippocampal Neurons by Memantine and Alpha7 Nicotinic Acetylcholine Receptor Ligands.
Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.
期刊介绍:
ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.