Zhao Qin, Tang Xi Can
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
Eur J Pharmacol. 2002 Nov 29;455(2-3):101-7. doi: 10.1016/s0014-2999(02)02589-x.
Five inhibitors of acetylcholinesterase, huperzine A, donepezil, tacrine, rivastigmine and physostigmine, were compared with regard to their effects on different molecular forms of acetylcholinesterase in cerebral cortex, hippocampus, and striatum from the rat brain. In general, huperzine A preferentially inhibited tetrameric acetylcholinesterase (G4 form), while tacrine and rivastigmine preferentially inhibited monomeric acetylcholinesterase (G1 form). Donepezil showed pronounced selectivity for G1 acetylcholinesterase in striatum and hippocampus, but not in cortex. Physostigmine showed no form-selectivity in any brain region. In cortex, the most potent inhibitors of G4 acetylcholinesterase were huperzine A (K(i) 7 x 10(-9) M) and donepezil (K(i) 4 x 10(-9) M). The potent inhibitors of cortical G1 acetylcholinesterase were donepezil (K(i) 3.5 x 10(-9) M) and tacrine (K(i) 2.3 x 10(-8) M). In hippocampus, huperzine A and physostigmine were the most potent inhibitors of G4 acetylcholinesterase, while donepezil and tacrine were most potent against G1 acetylcholinesterase. In striatum, huperzine A and donepezil were the most potent against G4 acetylcholinesterase, while again donepezil was the most potent against G1. Although the inhibition constants (K(i)) of these acetylcholinesterase inhibitors differed significantly from region to region, the nature of the inhibition did not vary. These results suggest that the use of acetylcholinesterase inhibitors in treatment of Alzheimer's disease must consider both form-specific and region-specific characteristics of acetylcholinesterase inhibition.
比较了五种乙酰胆碱酯酶抑制剂，石杉碱甲、多奈哌齐、他克林、卡巴拉汀和毒扁豆碱，研究它们对大鼠大脑皮质、海马体和纹状体中不同分子形式的乙酰胆碱酯酶的作用。总体而言，石杉碱甲优先抑制四聚体乙酰胆碱酯酶（G4形式），而他克林和卡巴拉汀优先抑制单体乙酰胆碱酯酶（G1形式）。多奈哌齐在纹状体和海马体中对G1乙酰胆碱酯酶表现出明显的选择性，但在皮质中没有。毒扁豆碱在任何脑区均未表现出形式选择性。在皮质中，G4乙酰胆碱酯酶的最有效抑制剂是石杉碱甲（抑制常数Ki为7×10⁻⁹M）和多奈哌齐（Ki为4×10⁻⁹M）。皮质G1乙酰胆碱酯酶的有效抑制剂是多奈哌齐（Ki为3.5×10⁻⁹M）和他克林（Ki为2.3×10⁻⁸M）。在海马体中，石杉碱甲和毒扁豆碱是G4乙酰胆碱酯酶的最有效抑制剂，而多奈哌齐和他克林对G1乙酰胆碱酯酶最有效。在纹状体中，石杉碱甲和多奈哌齐对G4乙酰胆碱酯酶最有效，而多奈哌齐对G1乙酰胆碱酯酶仍是最有效。尽管这些乙酰胆碱酯酶抑制剂的抑制常数（Ki）在不同脑区有显著差异，但抑制的性质没有变化。这些结果表明，在治疗阿尔茨海默病时使用乙酰胆碱酯酶抑制剂必须考虑乙酰胆碱酯酶抑制的形式特异性和区域特异性特征。
