Adem A, Mohammed A K, Winblad B
Department of Geriatric Medicine, Karolinska Institute, Huddinge Hospital, Sweden.
J Neural Transm Park Dis Dement Sect. 1990;2(2):113-28. doi: 10.1007/BF02260899.
9-Amino-1,2,3,4-tetrahydroaminoacridine (THA) in combination with lecithin has been reported to improve the memory of Alzheimer's disease patients. We have examined some properties of THA in vitro and in vivo so as to define some of the mechanism(s) by which THA might produce its therapeutic effects. In vitro, THA was more potent at inhibiting human plasma cholinesterase (IC50 = 0.03 microM) than human erythrocyte acetylcholinesterase (IC50 = 0.3 microM) and rat brain acetylcholinesterase (IC50 = 0.32 microM). Radioligand binding studies indicated that THA binds reversibly and competitively to primary M1 and M2 human cortical muscarinic receptors with similar affinities. Moreover, THA showed similar affinity for temporal cortices muscarinic receptors from Alzheimer and non-Alzheimer (control) brains. In vivo, subcutaneous administration of THA (1-8 mg/kg body weight) to adult rats (6 months old) produced a dose dependent decrease in general activity compared to saline-treated rats. However, at a concentration of 0.5 mg/kg body weight, the general activity of the rats was increased compared to saline-treated rats. The cognitive function of the THA-treated adult rats (subcutaneously 2 mg/kg body weight) was not significantly improved compared to saline-treated rats. It is concluded that the mechanisms of action of THA on the cholinergic system involve reversible inhibition of cholinesterases and reversible and competitive interaction with muscarinic acetylcholine receptors. These effects might be of therapeutic value in the treatment of Alzheimer's disease.
据报道，9-氨基-1,2,3,4-四氢吖啶（THA）与卵磷脂联合使用可改善阿尔茨海默病患者的记忆力。我们已经在体外和体内研究了THA的一些特性，以确定THA可能产生治疗效果的某些机制。在体外，THA抑制人血浆胆碱酯酶（IC50 = 0.03 microM）的效力比抑制人红细胞乙酰胆碱酯酶（IC50 = 0.3 microM）和大鼠脑乙酰胆碱酯酶（IC50 = 0.32 microM）更强。放射性配体结合研究表明，THA以相似的亲和力与主要的M1和M2人皮质毒蕈碱受体可逆性地竞争性结合。此外，THA对来自阿尔茨海默病和非阿尔茨海默病（对照）脑的颞叶皮质毒蕈碱受体表现出相似的亲和力。在体内，给成年大鼠（6个月大）皮下注射THA（1 - 8 mg/kg体重），与盐水处理的大鼠相比，其一般活动产生剂量依赖性降低。然而，在0.5 mg/kg体重的浓度下，与盐水处理组相比，大鼠的一般活动增加。与盐水处理的大鼠相比，皮下注射2 mg/kg体重THA的成年大鼠的认知功能没有显著改善。结论是，THA对胆碱能系统的作用机制包括对胆碱酯酶的可逆性抑制以及与毒蕈碱型乙酰胆碱受体的可逆性和竞争性相互作用。这些作用可能对阿尔茨海默病的治疗具有治疗价值。
