Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates

Patrick Michael Callahan, Elizabeth J. Hutchings, Nancy J. Kille, James M. Chapman, Alvin V Terry

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.

Original languageEnglish (US)
Pages (from-to)201-212
Number of pages12
JournalNeuropharmacology
Volume67
DOIs
StatePublished - Apr 1 2013

Fingerprint

Nicotinic Receptors
Primates
Rodentia
Learning
Cholinesterase Inhibitors
Alzheimer Disease
Cognition Disorders
Maze Learning
Therapeutics
Memory Disorders
Task Performance and Analysis
Drug Combinations
Macaca mulatta
Short-Term Memory
Animal Models
donepezil
1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea
Water
Pharmaceutical Preparations
Population

Keywords

  • Aging
  • Alzheimer's disease
  • Cholinergic
  • Memory
  • Mild cognitive impairment
  • Pro-cognitive

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

@article{445e11a5dd0d43fe9d1c62894d908f2b,
title = "Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates",
abstract = "The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.",
keywords = "Aging, Alzheimer's disease, Cholinergic, Memory, Mild cognitive impairment, Pro-cognitive",
author = "Callahan, {Patrick Michael} and Hutchings, {Elizabeth J.} and Kille, {Nancy J.} and Chapman, {James M.} and Terry, {Alvin V}",
year = "2013",
month = "4",
day = "1",
doi = "10.1016/j.neuropharm.2012.10.019",
language = "English (US)",
volume = "67",
pages = "201--212",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates

AU - Callahan, Patrick Michael

AU - Hutchings, Elizabeth J.

AU - Kille, Nancy J.

AU - Chapman, James M.

AU - Terry, Alvin V

PY - 2013/4/1

Y1 - 2013/4/1

N2 - The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.

AB - The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age.

KW - Aging

KW - Alzheimer's disease

KW - Cholinergic

KW - Memory

KW - Mild cognitive impairment

KW - Pro-cognitive

UR - http://www.scopus.com/inward/record.url?scp=84873355827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873355827&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2012.10.019

DO - 10.1016/j.neuropharm.2012.10.019

M3 - Article

VL - 67

SP - 201

EP - 212

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -