The effects of JWB1-84-1 on memory-related task performance by amyloid Abeta transgenic mice and by young and aged monkeys.
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.
Sood
Ajay
A
Alzheimer's Research Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA.
Warren Beach
J
J
Webster
Scott J
SJ
Terry
Alvin V
AV
Buccafusco
Jerry J
JJ
D000375:Aging / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001923:Brain Chemistry / Q000187:drug effects; D003624:Darkness; D004305:Dose-Response Relationship, Drug; D005260:Female; D018737:Hand Strength / Q000502:physiology; D008027:Light; D008253:Macaca mulatta; D008254:Macaca nemestrina; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; C525664:JWB-1-84-1; D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines