Sood Ajay, Warren Beach J, Webster Scott J, Terry Alvin V, Buccafusco Jerry J
Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
Neuropharmacology. 2007 Oct;53(5):588-600. doi: 10.1016/j.neuropharm.2007.06.028. Epub 2007 Jul 14.
JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with expectation that they would be high potency compounds for cytoprotection. As one of the more potent analogs in this regard, JWB1-84-1, a piperazine derivative, was selected for testing as a cognition-enhancing agent. The compound was evaluated for efficacy in Alzheimer's disease transgenic mice (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J). A separate cohort of mice (AD Tg) were first subjected to a behavioral test battery in which the transgenic strain was compared with the wild-type strain. AD Tg mice were shown to exhibit specific deficits in the acquisition of a working memory (5-trial/session radial arm water maze, RAWM) task at a time when the animals exhibited maximal cerebral amyloid burden. JWB1-84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice the RAWM task that was maximal after the 20 microg/kg dose. Aged macaques (20-32 y) were trained to proficiency in their performance of a computer-assisted delayed matching-to-sample task. Vehicle (normal saline) or JWB1-84-1 (5-150 microg/kg, i.m.) was administered 10 min before the initiating of testing. On average, JWB1-84-1 treatment significantly improved task accuracy after all but the lowest dose. The maximal degree of improvement was attained after animals received the 100 microg/kg dose. The drug's effects were restricted primarily to Medium and Long delay trials - the most difficult portions of the task, which were improved by up to 18% above control. In young macaques JWB1-84-1 treatment also significantly reversed the decrements in task accuracy associated with the random presentation of a task distractor. Thus JWB1-84-1exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action might also work to slow the progression of Alzheimer's disease.
JWB1-84-1是50种胆碱叔胺类似物之一，合成这些类似物的目的是期望它们成为具有高效细胞保护作用的化合物。作为这方面更有效的类似物之一，哌嗪衍生物JWB1-84-1被选作认知增强剂进行测试。该化合物在阿尔茨海默病转基因小鼠（B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J）中评估疗效。另一组小鼠（AD转基因小鼠）首先接受一系列行为测试，将转基因品系与野生型品系进行比较。结果显示，在动物脑淀粉样蛋白负荷达到最大时，AD转基因小鼠在工作记忆（5次/组放射状臂水迷宫，RAWM）任务的获取方面表现出特定缺陷。JWB1-84-1使训练有素的AD转基因小鼠在RAWM任务中犯错误的数量呈剂量依赖性减少，在20微克/千克剂量后达到最大效果。对成年猕猴（20 - 32岁）进行训练，使其熟练完成计算机辅助延迟匹配样本任务。在测试开始前10分钟给予溶剂（生理盐水）或JWB1-84-1（5 - 150微克/千克，肌肉注射）。平均而言，除最低剂量外，JWB1-84-1治疗均显著提高了任务准确性。在动物接受100微克/千克剂量后，改善程度达到最大。药物的作用主要局限于中延迟和长延迟试验——任务中最困难的部分，比对照组提高了多达18%。在幼年猕猴中，JWB1-84-1治疗也显著逆转了与任务干扰物随机呈现相关的任务准确性下降。因此，JWB1-84-1具有治疗与神经退行性疾病和注意力缺陷障碍相关的认知症状的潜力。其细胞保护作用也可能有助于减缓阿尔茨海默病的进展。
