Nordberg A, Nilsson-Håkansson L, Adem A, Lai Z, Winblad B
Department of Pharmacology, Uppsala University, Sweden.
Prog Clin Biol Res. 1989;317:1169-78.
1,2,3,4-tetrahydro-9-aminoacridine (THA) is a cholinesterase inhibitor presently under investigation in clinical trials for treatment of Alzheimer's disease, senile dementia of Alzheimer type (AD/SDAT). To further analyse the underlying mechanisms for its effect in human brain, an in vitro model which allows measurement of acetylcholine (ACh) release from human postmortem brain slices has been used. In control cortical tissue THA induces a decreased release of ACh probably due to negative feedback mechanisms mediated via presynaptic muscarinic autoreceptors. In AD/SDAT cortex THA enhances the release of ACh to control level. This effect is prevented by nicotinic or muscarinic receptor antagonists, which suggest receptor mechanisms involving both nicotinic and muscarinic receptors. Subchronic treatment of rats with THA (10 mg/kg sc twice daily) or physostigmine (0.9 mg/kg sc five times daily) causes a significant increase in the number of high affinity nicotinic receptors in the cortex of THA treated rats whereas no change is found in the physostigmine treated rats. The number of muscarinic receptors are decreased following both THA and physostigmine treatment.
1,2,3,4-四氢-9-氨基吖啶（THA）是一种胆碱酯酶抑制剂，目前正处于治疗阿尔茨海默病、阿尔茨海默型老年痴呆症（AD/SDAT）的临床试验研究中。为了进一步分析其对人脑作用的潜在机制，已使用一种体外模型来测量人死后脑切片中乙酰胆碱（ACh）的释放。在对照皮质组织中，THA可能通过突触前毒蕈碱自身受体介导的负反馈机制诱导ACh释放减少。在AD/SDAT皮质中，THA将ACh释放增强至对照水平。烟碱或毒蕈碱受体拮抗剂可阻止这种效应，这表明受体机制涉及烟碱和毒蕈碱受体。用THA（10mg/kg皮下注射，每日两次）或毒扁豆碱（0.9mg/kg皮下注射，每日五次）对大鼠进行亚慢性治疗，可使THA治疗组大鼠皮质中高亲和力烟碱受体数量显著增加，而毒扁豆碱治疗组大鼠未发现变化。THA和毒扁豆碱治疗后毒蕈碱受体数量均减少。
