Rakonczay Z
Alzheimer's Disease Research Center, Department of Psychiatry, University of Szeged, Szeged, Hungary.
Acta Biol Hung. 2003;54(2):183-9. doi: 10.1556/ABiol.54.2003.2.7.
Eight inhibitors of acetylcholinesterase (AChE), tacrine, bis-tacrine, donepezil, rivastigmine, galantamine, heptyl-physostigmine, TAK-147 and metrifonate, were compared with regard to their effects on AChE and butyrylcholinesterase (BuChE) in normal human brain cortex. Additionally, the IC50 values of different molecular forms of AChE (monomeric, G1, and tetrameric, G4) were determined in the cerebral cortex in both normal and Alzheimer's human brains. The most selective AChE inhibitors, in decreasing sequence, were in order: TAK-147, donepezil and galantamine. For BuChE, the most specific was rivastigmine. However, none of these inhibitors was absolutely specific for AChE or BuChE. Among these inhibitors, tacrine, bis-tacrine, TAK-147, metrifonate and galantamine inhibited both the G1 and G4 AChE forms equally well. Interestingly, the AChE molecular forms in Alzheimer samples were more sensitive to some of the inhibitors as compared with the normal samples. Only one inhibitor, rivastigmine, displayed preferential inhibition for the G1 form of AChE. We conclude that a molecular form-specific inhibitor may have therapeutic applications in inhibiting the G1 form, which is relatively unchanged in Alzheimer's brain.
在正常人类大脑皮层中，对8种乙酰胆碱酯酶（AChE）抑制剂，即他克林、双他克林、多奈哌齐、卡巴拉汀、加兰他敏、庚基毒扁豆碱、TAK - 147和美曲膦酯，就其对AChE和丁酰胆碱酯酶（BuChE）的作用进行了比较。此外，还测定了正常人和阿尔茨海默病患者大脑皮层中不同分子形式的AChE（单体形式G1和四聚体形式G4）的半数抑制浓度（IC50）值。选择性最高的AChE抑制剂，按降序排列依次为：TAK - 147、多奈哌齐和加兰他敏。对于BuChE而言，最具特异性的是卡巴拉汀。然而，这些抑制剂中没有一种对AChE或BuChE具有绝对特异性。在这些抑制剂中，他克林、双他克林、TAK - 147、美曲膦酯和加兰他敏对G1和G4两种AChE形式的抑制效果相当。有趣的是，与正常样本相比，阿尔茨海默病样本中的AChE分子形式对某些抑制剂更为敏感。只有一种抑制剂卡巴拉汀对AChE的G1形式表现出优先抑制作用。我们得出结论，一种分子形式特异性抑制剂可能在抑制G1形式方面具有治疗应用价值，而G1形式在阿尔茨海默病大脑中相对未发生变化。
