Cytoprotective and cognitive enhancing properties of JWB1-84-1

Abstract

JWB 1-84-1 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, JWB 1-84-1, 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, PSENldE9)85Dbo/J). The mice (AJ? Tg) were first subjected t9 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. JWB 1-84-1 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 μg/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 JWB 1- 84-1 (5-150 ~tg/kg, i.m.) w~s adip.inistered 10 min before the initiating of testing. On average, JWB 1-84-1 treatment significantly improved task accuracy after all but-the lowest dose. JWB 1-84-1 showed cytoprotection in .a dose dependent manner in NGF withdrawal model of cytotoxicity in differentiated PC-12 cells. Additionally, JWBl-84- 1, at the high concentrat~on caused increase in intracellular Ca + 2 in primary cultured hippocampal as well as cortical neurons by acting di;ectly ~n an intracellular Ca +2 . store. Thus JWB 1-84-1 exhibits th~ potential for treating the cognitive symptoms associated with neurodegenerativ~ diseases and attention deficit disorders. Its cytoprotective action also might work to slow the progression of neurodegenerative diseases such as Alzheimer's disease.