Li Juan, Huang Hong, Miezan Ezoulin Jean-Marc, Gao Xiao-Ling, Massicot France, Dong Chang-Zhi, Heymans Françoise, Chen Hong-Zhuan
Department of Pharmacology, College of Basic Medical Sciences, Shanghai Jiaotong University, Shanghai, PR China.
Int J Neuropsychopharmacol. 2007 Feb;10(1):21-9. doi: 10.1017/S1461145705006425. Epub 2006 Jan 23.
The key pathophysiological mechanisms in Alzheimer's disease involve the selective loss of cholinergic neurons and pro-inflammatory mediator-related chronic inflammatory responses in the brain, therefore interventions of these processes are crucial to the treatment of this disease. In the present study, the pharmacological profile of PMS777, a new acetylcholinesterase (AChE) inhibitor with platelet-activating factor (PAF) antagonistic activity, has been evaluated in vitro and in vivo. PMS777 (1-100 microM) dose-dependently inhibited PAF-induced rabbit platelet aggregation by competing with [3H]PAF for its receptor on platelets, and protected a human neuroblastoma cell line SH-SY5Y against PAF-induced neurotoxicity. Moreover, it markedly inhibited brain AChE activity in mice and showed a modest selectivity for AChE (AChE: IC50=2.48+/-0.12 microM; butyrylcholinesterase: IC50=4.47+/-0.15 microM). Ex vivo, PMS777 (5, 10, 20 or 40 mg/kg i.p.) reduced brain AChE activity in a dose-dependent manner. In-vivo studies revealed that PMS777 (0.25, 0.5, 1, 2.5 or 5 mg/kg i.p.) could reverse scopolamine-induced memory retrieval deficits in mice, and displayed a typical bell-shaped dose-response relationship. Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimer's disease.
阿尔茨海默病的关键病理生理机制涉及大脑中胆碱能神经元的选择性丧失以及与促炎介质相关的慢性炎症反应，因此对这些过程进行干预对于该疾病的治疗至关重要。在本研究中，已在体外和体内评估了新型乙酰胆碱酯酶（AChE）抑制剂PMS777的药理学特性，该抑制剂具有血小板活化因子（PAF）拮抗活性。PMS777（1 - 100 microM）通过与[3H]PAF竞争其在血小板上的受体，剂量依赖性地抑制PAF诱导的兔血小板聚集，并保护人神经母细胞瘤细胞系SH - SY5Y免受PAF诱导的神经毒性。此外，它显著抑制小鼠脑中的AChE活性，并且对AChE表现出适度的选择性（AChE：IC50 = 2.48 +/- 0.12 microM；丁酰胆碱酯酶：IC50 = 4.47 +/- 0.15 microM）。在体外，PMS777（5、10、20或40 mg/kg腹腔注射）以剂量依赖性方式降低脑AChE活性。体内研究表明，PMS777（0.25、0.5、1、2.5或5 mg/kg腹腔注射）可逆转东莨菪碱诱导的小鼠记忆恢复缺陷，并呈现典型的钟形剂量 - 反应关系。综上所述，这些结果表明PMS777具有PAF受体拮抗和AChE抑制双重活性，表明该化合物可能是用于阿尔茨海默病治疗相关进一步研究的有前景的先导化合物。
