The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs.
For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.
Studzinski
Christa M
CM
Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8. c.studzinski@utoronto.ca
Araujo
Joseph A
JA
Milgram
Norton W
NW
D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D003704:Dementia / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D015203:Reproducibility of Results; D013997:Time Factors
D002800:Cholinesterase Inhibitors