| JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with the 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). The 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 (radial arm water maze) task at a time when the animals exhibited maximal cerebral amyloid plaque burden. JWB1-84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice in a 5-trial/session radial arm water maze task that was maximal after the 20 mug/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 mug/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. JWB1-84-1 showed cytoprotection in a dose dependent manner in NGF withdrawal model of cytotoxicity in differentiated PC-12 cells. Additionally, JWB1-84-1, at the high concentration caused increase in intracellular Ca+2 in primary cultured hippocampal as well as cortical neurons by acting directly on an intracellular Ca+2 store. Thus JWB1-84-1 exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action also might work to slow the progression of neurodegenerative diseases such as Alzheimer's disease.;INDEX WORDS: Alzheimer's disease, Cytoprotection, Cognitive Enhancement, Choline Analogs, Nicotinic Receptors, Delayed Matching to Sample, Radial Arm Water Maze, Intracellular Calcium. |
