The effects of JWB1-84-1 on memory-related task performance by amyloid Aβ transgenic mice and by young and aged monkeys

Abstract

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 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 JWB1-84-1 (5–150 μg/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 μg/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.

Introduction

Alzheimer's disease (AD) is characterized by neurodegeneration, dementia, and other behavioral abnormalities. Drug discovery for the treatment of AD has uncovered a wide variety of potential drug targets for treatment of cognitive impairment (Buccafusco and Terry, 2000, Youdim and Buccafusco, 2005). However, there presently exist only a limited number of therapeutic agents available for AD. Pharmacological treatment of AD focuses on symptomatic improvements with little potential to modify the course of the disease. Thus, there continues to be interest in developing multiple functional drugs that combine two or more therapeutic properties such as cognition enhancement and neuroprotection (Buccafusco and Terry, 2000, Youdim and Buccafusco, 2005). With this concept in mind we have hypothesized that the naturally occurring quaternary amine, choline could serve as a prototypical member of such a class of agents since, in addition to its well known role as a precursor to the neurotransmitter acetylcholine, choline has been described as a full (but low potency) agonist at the α7 subtype of nicotinic acetylcholine receptors (Papke et al., 1996, Alkondon et al., 1997). The latter pharmacological property has been associated with the ability of nicotine and other related α7 receptor agonists to improve working memory in a variety of rodent and non-human primate models, as well as to function as a neuroprotective agent (Elrod et al., 1988, Buccafusco and Jackson, 1991, Jonnala and Buccafusco, 2001, Levin, 2002, Li and Buccafusco, 2003). To date, we have synthesized over 50 analogs of choline that were shown to have varying abilities to produce cytoprotection in differentiated PC-12 cells. JWB1-84-1, a piperazine derivative, was shown to be approximately equipotent with nicotine in a cytoprotection assay (Buccafusco, 2004).

Though we later determined that JWB-1-84-1 was not an agonist for nicotinic receptors, because of its effectiveness in the cytoprotection assay we elected to evaluate the drug for its ability to improve cognition in animal models. JWB1-84-1 was first examined in the (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) transgenic mouse model of AD. These mice harbor the Swedish mutation of the amyloid precursor protein gene and the deletion of exon 9 in the presenilin-1 gene. These mutations were identified in the familial early onset form of AD and they are known to lead to exaggerated deposition of cerebral amyloid plaques (Borchelt et al., 1997, Jankowsky et al., 2004). These AD Tg mice develop mature cerebral amyloid deposits at about 6–7 months of age. They also exhibit impairment in the performance of various memory related behavioral tasks 10–12 months of age as compared to their wild type littermates (Savonenko et al., 2005).

In this study we used the radial arm water maze (RAWM) to assess spatial working memory in the mice (Arendash et al., 2001, Hyde et al., 1998, Savonenko et al., 2005). Part of the relevance of this model derives from the finding that spatial working memory is known to deteriorate during early stages of AD (Christensen et al., 1998, White and Murphy, 1998). Initially we considered using the spatial reference memory paradigm in the Morris water maze, and though AD Tg mice were impaired in task acquisition relative to their wild-type litter maters, we encountered high inter- and intra-subject variability (data not shown). Reduced variability and the ability to use each mouse in a complete dose regimen prompted our decision to use the RAWM task for the drug studies in mice.

JWB1-84-1 also was evaluated for efficacy as a cognition enhancing agent in 20–32 year old aged Rhesus monkeys who were well trained in the performance of a computer-assisted delayed matching-to-sample task (DMTS). A version of the DMTS task that featured the random presentation of task-relevant distractors (Prendergast et al., 1998, Paule et al., 1998) also was used to evaluate the potential of JWB1-84-1 to reverse distractor-impaired task accuracies. The DMTS task as we use it in aged monkeys has been validated on numerous occasions as a relevant method for predicting the clinical utility of potential memory-enhancing agents (Buccafusco et al., 2003b, Buccafusco et al., 2005b, Buccafusco and Terry, 2000, Paule et al., 1998, Terry et al., 2002a).

In this study, we show that acute administration of JWB1-84-1 in AD Tg mice and in aged non-human primates improves their performance accuracies in working memory tasks in both species as compared to their respective vehicle-treated controls. In monkeys the improvements in task accuracies noted during sessions run just after drug administration of JWB-1-84-1 were also observed during sessions run 24 h later.