title: Positive allosteric modulator of α7 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.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hutchings
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Kille
authors.forename: James M
authors.initials: JM
authors.lastname: Chapman
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D000077265:Donepezil; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007189:Indans / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013045:Species Specificity; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D002800:Cholinesterase Inhibitors; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D007189:Indans; D007555:Isoxazoles; D010671:Phenylurea Compounds; D010880:Piperidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil