Bis（7）-tacrine对NMDA受体的作用及其机制研究
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摘要
第一部分Tacrine,memantine和bis(7)-tacrine对培养大鼠海马神经元NMDA电流抑制作用比较
阿尔茨海默病(Alzheimer’s disease,AD)发病机制与胆碱能神经元功能缺损以及神经元凋亡均有密切关系。在治疗AD,特别是防止AD及其它神经退行性病变方面,兼具抗凋亡作用的乙酰胆碱酯酶抑制剂如bis(7)-tacrine将会比单纯的乙酰胆碱酯酶抑制剂发挥更有效的作用。本实验通过膜片钳技术,利用原代培养的大鼠海马神经元,将bis(7)-tacrine与tacrine和memantine对N-methyl-D-aspartate(NMDA)电流的抑制作用做比较,并进一步研究bis(7)-tacrinec对NMDA受体的作用机制。结果显示,三种药物均选择性地作用于NMDA受体,浓度依赖性地抑制NMDA电流,其IC50值分别为3.61±0.78μM,112.33±19.83μM和8.82±1.03μM。Tacrine和memantine均为“开放通道阻滞剂”,作用于NMDA受体通道的内部,表现为“激动剂依赖性”和“电压依赖性”;前者与NMDA受体结合与解离的速度更快,25μM以上浓度tacrine与NMDA同时作用时,停药后产生一内向延迟电流峰。而bis(7)-tacrine对NMDA电流的抑制作用不同于tacrine和memantine,提前1 s给药能明显提高bis(7)-tacrine的抑制作用,但提前更长时间(2-90 s)并无进一步抑制。在钳制电压-50至+50mV的范围内,bis(7)-tacrine对NMDA电流的抑制率没有变化,I-V曲线的翻转电位也没有改变。Bis(7)-tacrine没有明显改变NMDA的EC50值[49.48±2.93μM in the absence of bis(7)-tacrine vs 57.32±8.43μM in the presence of bis(7)-tacrine;ANOVA,P﹥0.05;n = 7-8],但使NMDA最大反应浓度(Emax)降低了约40%(ANOVA,P﹤0.05;n = 7-8),显示bis(7)-tacrine的作用为非竞争性地抑制NMDA激活电流。结果提示,作为一种新型二聚体胆碱酯酶抑制剂,bis(7)-tacrine对NMDA激活电流的的抑制作用强于tacrine和memantine,其作用机制也与它们不同,是以慢作用方式、非竞争性地抑制NMDA激活电流,其临床使用的效能和安全性可能较高。
第二部分Bis(7)-tacrine对培养大鼠海马神经元NMDA受体可能的作用位点研究
最近的研究证实,bis(7)-tacrine除作为一种乙酰胆碱酯酶抑制剂外,还可通过抑制原代培养大鼠小脑颗粒细胞NMDA受体而防止谷氨酸导致的神经元凋亡。本实验通过全细胞膜片钳记录研究bis(7)-tacrine对原代培养大鼠海马神经元NMDA受体可能的作用位点。结果发现,细胞外液中甘氨酸的浓度从0.1μM增加至10μM,细胞外液pH值从8.1改变到6.7,在细胞外液中加入二硫苏糖醇(2 mM)、精胺(10μM)、镁离子(10至100μM)或锌离子(5至20μM)均不引起bis(7)-tacrine对NMDA电流抑制率的改变。电极内液中加入25μM bis(7)-tacrine也未观察到外加的2.5μM bis(7)-tacrine对30μM NMDA激活电流抑制率的改变(37±3% vs对照组36±4%,P﹥0.05;n = 4)。但是,2.5μM bis(7)-tacrine及5μM dizocilpine(MK-801)分别对30μM NMDA激活电流抑制了36%和22%,而在两种药物都存在的条件下,30μM NMDA电流仅被抑制了37%。结果提示, bis(7)-tacrine虽然不大可能作用于MK-801位点,但MK-801却可以负性调制bis(7)-tacrine对NMDA受体的抑制作用。
第三部分Bis(7)-tacrine对表达NR1/NR2A或NR1/NR2B受体的HEK-293细胞NMDA电流抑制作用
在正常大鼠前脑,NMDA受体复合物的构成形式主要是NR1/NR2A和NR1/NR2B的二合体形式,少部分以NR1/NR2A/NR2B的三合体形式存在。因此,我们进一步通过表达NR1/NR2A或NR1/NR2B受体到培养的HEK-293细胞,利用膜片钳技术来研究bis(7)-tacrine对NMDA电流的抑制作用。结果显示,在同时给药的情况下,作用于表达了NR1/NR2A受体的HEK-293细胞时,1μM bis(7)-tacrine对30μM NMDA和1000μM NMDA激活稳态电流的抑制分别为46%和40%(ANOVA,P﹥0.05;n = 5),显示其作用方式可能与NMDA浓度无关,可能为非竞争性抑制;而作用于表达了NR1/NR2B受体的HEK-293细胞时,1μM bis(7)-tacrine对NMDA电流的抑制与NMDA浓度有关,对30μM NMDA和1000μM NMDA激活稳态电流的抑制分别为61%和13%(ANOVA,P﹤0.05;n = 6),这似乎是一种竞争性的作用方式。但在1000μM NMDA作用条件下,同时给予1μM bis(7)-tacrine对NMDA激活电流峰值产生了一定的抑制作用,电流逐渐下降到稳态,而在同一细胞上提前5秒给予1μM bis(7)-tacrine却可以将峰值几乎完全抑制。这一结果表明,bis(7)-tacrine对表达NR1/NR2B受体NMDA电流的抑制作用可能为慢作用方式,并不依赖于激动剂的存在。钳制电压从-50到+50mV变动范围内,bis(7)-tacrine对NMDA电流的抑制率没有发生变化,而且其翻转电位没有改变。这些结果与我们前面用培养的海马神经元实验结果趋于一致,证明bis(7)-tacrine作用于表达的NR1/NR2B受体时,还是以非竞争性方式,无激动剂依赖性和电压依赖性,并且对离子的通透没有发生选择性变化。结果提示:在作用于表达了NR1/NR2A或NR1/NR2B的HEK-293细胞时,bis(7)-tacrine仍然以非竞争性方式抑制NMDA电流,可以此为模型进一步开展有关其分子机制的实验研究。
Part 1 Comparison of the inhibition by tacrine, memantine and bis(7)-tacrine of N-methyl-D-aspartate-activated currents in cultured rat hippocampal neurons
The cellular mechanism of Alzheimer’s disease (AD) is closely related to cholinergic disfunction and neuronal apoptosis. In treating AD, especially in preventing AD and other neurodegenerative diseases, acetylcholinesterase inhibitors, such as bis(7)-tacrine, which possess anti-apoptosis functions should be more effective than compounds that only have pure acetylcholinesterase inhibitory properties. The present study was carried out to determine the inhibitory mechanisms of bis(7)-tacrine by comparing it with tacrine and memantine in primary cultured rat hippocampal neurons using whole-cell patch-clamp techniques. The results indicate that, all three drugs selectively produced a concentration-dependent inhibition of NMDA-activated current (IC50 values of 3.61±0.78μM, 112.33±19.83μM, 8.82±1.03μM for bis(7)-tacrine, tacrine and memantine, respectively). Both tacrine and memantine were‘open channel blockers’, acted at the inner of NMDA receptor channels, showing‘agonist-dependency’and‘voltage-dependency’. The former had quicker association and disassociation rate with NMDA receptor than the latter. Tacrine at a concentration above 25μM inhibited NMDA-evoked current by enhancing receptor desensitization, followed by a delayed current peak just after cessation of drug application. However, the inhibition of NMDA-activated currents by bis(7)-tacrine was different from that of tacrine and memantine: inhibition was enhanced largely by 1 s preapplication of bis(7)-tacrine, but longer preapplication (2-90 s) had no more inhibitory effect. The percentage inhibition of NMDA-activated current by bis(7)-tacrine was not significantly different at the holding potentials ranging from -50 to +50 mV, without changing the reversal potential too. Bis(7)-tacrine did not significantly change the EC_(50) value of NMDA-activated current [49.48±2.93μM in the absence vs 57.32±8.43μM in the presence of bis(7)-tacrine; ANOVA, P﹥0.05;n = 7-8], but decreased the E_(max) of NMDA current by 40% (ANOVA, P﹤0.05; n = 7-8), showing that the inhibition of NMDA-induced currnet by bis(7)-tacrine was non-competitive. These results also suggest that bis(7)-tacrine, a novel dimeric acetylcholinesterase inhibitor, more potently inhibits NMDA receptor function than tacrine and memantine by a slow onset, non-competitive mechanism, which may have better clinical efficiency and safety properties.
Part 2 Investigation of N-methyl-D-aspartate receptor modulatory sites possibly involved in the bis(7)-tacrine inhibition in cultured rat hippocampal neurons
Bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, has been proposed as one of the most promising agents to treat Alzheimer’s disease. Recently, the agent was found to prevent glutamate-induced neuronal apoptosis by inhibiting N-methyl-D-aspartate (NMDA) receptors in cultured rat cerebellar granule neurons in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the possible modulatory site of bis(7)-tacrine on NMDA receptors was investigated using whole-cell patch-clamp recording in cultured rat hippocampal neurons. The inhibitory rates of bis(7)-tacrine were neither altered by changing the concentrations of glycine (0.1-10μM) or proton (pH 8.1-6.7) in the external solution, nor by adding ditiothreitol (2 mM), spermine (10μM), Mg~(2+) (10-100μM), or Zn~(2+) (5-20μM) to the external solution. 25μM bis(7)-tacrine in the recording pipette solution did not alter the inhibition rate of 30μM NMDA-activated current by 2.5μM bis(7)-tacrine applied externally (37±3% vs coltrol of 36±4%, P﹥0.05; n = 4). However, 2.5μM bis(7)-tacrine and 5μM dizocilpine (MK-801) inhibited NMDA-activated currents by 36% and 22%, respectively; co-application of these two drugs only inhibited NMDA-activated currents by 37%. The results suggest that, although bis(7)-tacrine is very unlikely acting at the MK-801 site, MK-801 could negatively modulate the inhibition of NMDA receptor function by bis(7)-tacrine.
Part 3 Inhibition of N-methyl-D-aspartate-activated current by bis(7)-tacrine in HEK-293 cells expressing NR1/NR2A or NR1/NR2B receptors
In normal rat forebrain the NR1/NR2A and NR1/NR2B dimmers, but not the NR1/NR2A/NR2B trimer, are the main constitutional forms of NMDA receptors. The present study was carried out to determine the functional properties of heteromeric NMDA receptor subunits composed by NR1/NR2A or NR1/NR2B expressed in HEK- 293 cells and their inhibition by bis(7)-tacrine using whole-cell patch-clamp techniques. The results demonstrate that, when co-applied to HEK-293 cells expressing NR1/NR2A receptors, 1μM bis(7)-tacrine inhibited 30μM NMDA- and 1000μM NMDA-activated steady-state current by 46% and 40%, respectively (ANOVA, P﹥0.05; n = 5), suggesting that the inhibition of bis(7)-tacrine doesn’t depend on NMDA concentration which is consitant with a non-competitive mechanism of inhibition. But for the NR1/NR2B receptor, 1μM bis(7)-tacrine inhibited 30μM NMDA- and 1000μM NMDA-activated steady-state current by 61% and 13%, respectively (ANOVA, P﹤0.05; n = 6), showing that it appears to be competitive with NMDA. In addition, simultaneous application of 1μM bis(7)-tacrine and 1000μM NMDA produced a moderate inhibition of peak NMDA-activated current, followed a gradual decline of the current to a steady-state. However, when 1μM bis(7)-tacrine was applied for 5 s before NMDA, the peak current was almost completely inhibited. These results show that bis(7)-tacrine inhibition of NMDA current on NR1/NR2B was slow onset, and it did not depend on the existing of agonist. With holding potential ranging from -50 to +50 mV, the bis(7)-tacrine inhibition rate of NMDA current was the same, and the reversal potential did not change too. The results are consitant with what we have observed in cultured hippocampal neurons, showing that bis(7)-tacrine inhibits NR1/NR2B receptors in a non-competitive, agonist-independent and voltage-independent manner. These results also indicate that the NR1/NR2A and NR1/NR2B receptors could be used to study the molecular mechanism of bis(7)-tacrine inhibition.
阿尔茨海默病(Alzheimer’s disease,AD)发病机制与胆碱能神经元功能缺损以及神经元凋亡均有密切关系。在治疗AD,特别是防止AD及其它神经退行性病变方面,兼具抗凋亡作用的乙酰胆碱酯酶抑制剂如bis(7)-tacrine将会比单纯的乙酰胆碱酯酶抑制剂发挥更有效的作用。本实验通过膜片钳技术,利用原代培养的大鼠海马神经元,将bis(7)-tacrine与tacrine和memantine对N-methyl-D-aspartate(NMDA)电流的抑制作用做比较,并进一步研究bis(7)-tacrinec对NMDA受体的作用机制。结果显示,三种药物均选择性地作用于NMDA受体,浓度依赖性地抑制NMDA电流,其IC50值分别为3.61±0.78μM,112.33±19.83μM和8.82±1.03μM。Tacrine和memantine均为“开放通道阻滞剂”,作用于NMDA受体通道的内部,表现为“激动剂依赖性”和“电压依赖性”;前者与NMDA受体结合与解离的速度更快,25μM以上浓度tacrine与NMDA同时作用时,停药后产生一内向延迟电流峰。而bis(7)-tacrine对NMDA电流的抑制作用不同于tacrine和memantine,提前1 s给药能明显提高bis(7)-tacrine的抑制作用,但提前更长时间(2-90 s)并无进一步抑制。在钳制电压-50至+50mV的范围内,bis(7)-tacrine对NMDA电流的抑制率没有变化,I-V曲线的翻转电位也没有改变。Bis(7)-tacrine没有明显改变NMDA的EC50值[49.48±2.93μM in the absence of bis(7)-tacrine vs 57.32±8.43μM in the presence of bis(7)-tacrine;ANOVA,P﹥0.05;n = 7-8],但使NMDA最大反应浓度(Emax)降低了约40%(ANOVA,P﹤0.05;n = 7-8),显示bis(7)-tacrine的作用为非竞争性地抑制NMDA激活电流。结果提示,作为一种新型二聚体胆碱酯酶抑制剂,bis(7)-tacrine对NMDA激活电流的的抑制作用强于tacrine和memantine,其作用机制也与它们不同,是以慢作用方式、非竞争性地抑制NMDA激活电流,其临床使用的效能和安全性可能较高。
第二部分Bis(7)-tacrine对培养大鼠海马神经元NMDA受体可能的作用位点研究
最近的研究证实,bis(7)-tacrine除作为一种乙酰胆碱酯酶抑制剂外,还可通过抑制原代培养大鼠小脑颗粒细胞NMDA受体而防止谷氨酸导致的神经元凋亡。本实验通过全细胞膜片钳记录研究bis(7)-tacrine对原代培养大鼠海马神经元NMDA受体可能的作用位点。结果发现,细胞外液中甘氨酸的浓度从0.1μM增加至10μM,细胞外液pH值从8.1改变到6.7,在细胞外液中加入二硫苏糖醇(2 mM)、精胺(10μM)、镁离子(10至100μM)或锌离子(5至20μM)均不引起bis(7)-tacrine对NMDA电流抑制率的改变。电极内液中加入25μM bis(7)-tacrine也未观察到外加的2.5μM bis(7)-tacrine对30μM NMDA激活电流抑制率的改变(37±3% vs对照组36±4%,P﹥0.05;n = 4)。但是,2.5μM bis(7)-tacrine及5μM dizocilpine(MK-801)分别对30μM NMDA激活电流抑制了36%和22%,而在两种药物都存在的条件下,30μM NMDA电流仅被抑制了37%。结果提示, bis(7)-tacrine虽然不大可能作用于MK-801位点,但MK-801却可以负性调制bis(7)-tacrine对NMDA受体的抑制作用。
第三部分Bis(7)-tacrine对表达NR1/NR2A或NR1/NR2B受体的HEK-293细胞NMDA电流抑制作用
在正常大鼠前脑,NMDA受体复合物的构成形式主要是NR1/NR2A和NR1/NR2B的二合体形式,少部分以NR1/NR2A/NR2B的三合体形式存在。因此,我们进一步通过表达NR1/NR2A或NR1/NR2B受体到培养的HEK-293细胞,利用膜片钳技术来研究bis(7)-tacrine对NMDA电流的抑制作用。结果显示,在同时给药的情况下,作用于表达了NR1/NR2A受体的HEK-293细胞时,1μM bis(7)-tacrine对30μM NMDA和1000μM NMDA激活稳态电流的抑制分别为46%和40%(ANOVA,P﹥0.05;n = 5),显示其作用方式可能与NMDA浓度无关,可能为非竞争性抑制;而作用于表达了NR1/NR2B受体的HEK-293细胞时,1μM bis(7)-tacrine对NMDA电流的抑制与NMDA浓度有关,对30μM NMDA和1000μM NMDA激活稳态电流的抑制分别为61%和13%(ANOVA,P﹤0.05;n = 6),这似乎是一种竞争性的作用方式。但在1000μM NMDA作用条件下,同时给予1μM bis(7)-tacrine对NMDA激活电流峰值产生了一定的抑制作用,电流逐渐下降到稳态,而在同一细胞上提前5秒给予1μM bis(7)-tacrine却可以将峰值几乎完全抑制。这一结果表明,bis(7)-tacrine对表达NR1/NR2B受体NMDA电流的抑制作用可能为慢作用方式,并不依赖于激动剂的存在。钳制电压从-50到+50mV变动范围内,bis(7)-tacrine对NMDA电流的抑制率没有发生变化,而且其翻转电位没有改变。这些结果与我们前面用培养的海马神经元实验结果趋于一致,证明bis(7)-tacrine作用于表达的NR1/NR2B受体时,还是以非竞争性方式,无激动剂依赖性和电压依赖性,并且对离子的通透没有发生选择性变化。结果提示:在作用于表达了NR1/NR2A或NR1/NR2B的HEK-293细胞时,bis(7)-tacrine仍然以非竞争性方式抑制NMDA电流,可以此为模型进一步开展有关其分子机制的实验研究。
Part 1 Comparison of the inhibition by tacrine, memantine and bis(7)-tacrine of N-methyl-D-aspartate-activated currents in cultured rat hippocampal neurons
The cellular mechanism of Alzheimer’s disease (AD) is closely related to cholinergic disfunction and neuronal apoptosis. In treating AD, especially in preventing AD and other neurodegenerative diseases, acetylcholinesterase inhibitors, such as bis(7)-tacrine, which possess anti-apoptosis functions should be more effective than compounds that only have pure acetylcholinesterase inhibitory properties. The present study was carried out to determine the inhibitory mechanisms of bis(7)-tacrine by comparing it with tacrine and memantine in primary cultured rat hippocampal neurons using whole-cell patch-clamp techniques. The results indicate that, all three drugs selectively produced a concentration-dependent inhibition of NMDA-activated current (IC50 values of 3.61±0.78μM, 112.33±19.83μM, 8.82±1.03μM for bis(7)-tacrine, tacrine and memantine, respectively). Both tacrine and memantine were‘open channel blockers’, acted at the inner of NMDA receptor channels, showing‘agonist-dependency’and‘voltage-dependency’. The former had quicker association and disassociation rate with NMDA receptor than the latter. Tacrine at a concentration above 25μM inhibited NMDA-evoked current by enhancing receptor desensitization, followed by a delayed current peak just after cessation of drug application. However, the inhibition of NMDA-activated currents by bis(7)-tacrine was different from that of tacrine and memantine: inhibition was enhanced largely by 1 s preapplication of bis(7)-tacrine, but longer preapplication (2-90 s) had no more inhibitory effect. The percentage inhibition of NMDA-activated current by bis(7)-tacrine was not significantly different at the holding potentials ranging from -50 to +50 mV, without changing the reversal potential too. Bis(7)-tacrine did not significantly change the EC_(50) value of NMDA-activated current [49.48±2.93μM in the absence vs 57.32±8.43μM in the presence of bis(7)-tacrine; ANOVA, P﹥0.05;n = 7-8], but decreased the E_(max) of NMDA current by 40% (ANOVA, P﹤0.05; n = 7-8), showing that the inhibition of NMDA-induced currnet by bis(7)-tacrine was non-competitive. These results also suggest that bis(7)-tacrine, a novel dimeric acetylcholinesterase inhibitor, more potently inhibits NMDA receptor function than tacrine and memantine by a slow onset, non-competitive mechanism, which may have better clinical efficiency and safety properties.
Part 2 Investigation of N-methyl-D-aspartate receptor modulatory sites possibly involved in the bis(7)-tacrine inhibition in cultured rat hippocampal neurons
Bis(7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, has been proposed as one of the most promising agents to treat Alzheimer’s disease. Recently, the agent was found to prevent glutamate-induced neuronal apoptosis by inhibiting N-methyl-D-aspartate (NMDA) receptors in cultured rat cerebellar granule neurons in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the possible modulatory site of bis(7)-tacrine on NMDA receptors was investigated using whole-cell patch-clamp recording in cultured rat hippocampal neurons. The inhibitory rates of bis(7)-tacrine were neither altered by changing the concentrations of glycine (0.1-10μM) or proton (pH 8.1-6.7) in the external solution, nor by adding ditiothreitol (2 mM), spermine (10μM), Mg~(2+) (10-100μM), or Zn~(2+) (5-20μM) to the external solution. 25μM bis(7)-tacrine in the recording pipette solution did not alter the inhibition rate of 30μM NMDA-activated current by 2.5μM bis(7)-tacrine applied externally (37±3% vs coltrol of 36±4%, P﹥0.05; n = 4). However, 2.5μM bis(7)-tacrine and 5μM dizocilpine (MK-801) inhibited NMDA-activated currents by 36% and 22%, respectively; co-application of these two drugs only inhibited NMDA-activated currents by 37%. The results suggest that, although bis(7)-tacrine is very unlikely acting at the MK-801 site, MK-801 could negatively modulate the inhibition of NMDA receptor function by bis(7)-tacrine.
Part 3 Inhibition of N-methyl-D-aspartate-activated current by bis(7)-tacrine in HEK-293 cells expressing NR1/NR2A or NR1/NR2B receptors
In normal rat forebrain the NR1/NR2A and NR1/NR2B dimmers, but not the NR1/NR2A/NR2B trimer, are the main constitutional forms of NMDA receptors. The present study was carried out to determine the functional properties of heteromeric NMDA receptor subunits composed by NR1/NR2A or NR1/NR2B expressed in HEK- 293 cells and their inhibition by bis(7)-tacrine using whole-cell patch-clamp techniques. The results demonstrate that, when co-applied to HEK-293 cells expressing NR1/NR2A receptors, 1μM bis(7)-tacrine inhibited 30μM NMDA- and 1000μM NMDA-activated steady-state current by 46% and 40%, respectively (ANOVA, P﹥0.05; n = 5), suggesting that the inhibition of bis(7)-tacrine doesn’t depend on NMDA concentration which is consitant with a non-competitive mechanism of inhibition. But for the NR1/NR2B receptor, 1μM bis(7)-tacrine inhibited 30μM NMDA- and 1000μM NMDA-activated steady-state current by 61% and 13%, respectively (ANOVA, P﹤0.05; n = 6), showing that it appears to be competitive with NMDA. In addition, simultaneous application of 1μM bis(7)-tacrine and 1000μM NMDA produced a moderate inhibition of peak NMDA-activated current, followed a gradual decline of the current to a steady-state. However, when 1μM bis(7)-tacrine was applied for 5 s before NMDA, the peak current was almost completely inhibited. These results show that bis(7)-tacrine inhibition of NMDA current on NR1/NR2B was slow onset, and it did not depend on the existing of agonist. With holding potential ranging from -50 to +50 mV, the bis(7)-tacrine inhibition rate of NMDA current was the same, and the reversal potential did not change too. The results are consitant with what we have observed in cultured hippocampal neurons, showing that bis(7)-tacrine inhibits NR1/NR2B receptors in a non-competitive, agonist-independent and voltage-independent manner. These results also indicate that the NR1/NR2A and NR1/NR2B receptors could be used to study the molecular mechanism of bis(7)-tacrine inhibition.
引文
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