Horak Martin, Holubova Kristina, Nepovimova Eugenie, Krusek Jan, Kaniakova Martina, Korabecny Jan, Vyklicky Ladislav, Kuca Kamil, Stuchlik Ales, Ricny Jan, Vales Karel, Soukup Ondrej
Institute of Physiology, Academy of Sciences of the Czech Republic v.v.i., Videnska 1083, 14220 Prague 4, Czech Republic.
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 3;75:54-62. doi: 10.1016/j.pnpbp.2017.01.003. Epub 2017 Jan 13.
The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
他克林作为一种具有认知增强作用药物的机制被认为很复杂且尚未完全明确。据报道，其作用涉及广泛的靶点，包括胆碱能、γ-氨基丁酸能、一氧化氮能和谷氨酸能通路。在此，我们综述他克林及其衍生物对N-甲基-D-天冬氨酸受体（NMDAR）的影响，重点关注与阿尔茨海默病治疗相关的作用机制和生物学效应。我们的研究结果表明，他克林对谷氨酸能神经元的作用既有直接的也有间接的。体外研究常报道他克林具有直接的NMDAR拮抗作用；然而，这是在高浓度他克林条件下实现的，而临床情况下不太可能出现这种浓度。对记忆和行为测试的影响可归因于他克林通过M1受体激活影响NMDAR介导的电流所产生的间接作用，这会导致钙激活钾通道受到抑制。这种抑制会阻止膜复极化，导致NMDAR长期激活，进而引起长时程增强。基于这些研究结果，我们可以得出结论，具有双重胆碱酯酶和NMDAR调节活性的他克林衍生物可能是开发治疗与认知功能障碍相关疾病（如阿尔茨海默病）药物的一种有前景的方法。
