Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys.
Hepatotoxicity limits the clinical utility of the cholinesterase inhibitor tacrine as a palliative therapy for Alzheimer's disease. The present studies examined the effects of E2020, a selective acetylcholinesterase inhibitor not associated with liver toxicity in man, on cognitive performance in rhesus monkeys using tasks employed previously to evaluate tacrine and other cholinomimetic agents. The ability of E2020 to prevent the induction of a cognitive impairment by the muscarinic receptor antagonist scopolamine was assessed using an automated spatial delayed response task. Coadministration of E2020 (0.5-1.75 mg/kg) caused a dose-dependent reversal of the scopolamine (0.03 mg/kg) induced impairment observed after retention intervals of 10 and 20 s. At the highest dose of E2020 examined (1.75 mg/kg), choice accuracy approached normal control levels. In this dose range, E2020 was well tolerated, but at the higher dose of 2 mg/kg, cholinergic side-effects were apparent. The effect of E2020 on choice accuracy in a visual recognition task was also assessed as this task does not require the use of scopolamine to disrupt performance and beneficial effects of cholinomimetics can therefore be detected at lower doses than in the spatial memory paradigm. In this task, administration of E2020 increased choice accuracy from 59 +/- 1% correct to up to 71 +/- 2% at doses of 0.03 and 0.05 mg/kg. No observable adverse effects were induced by E2020 in this dose range. The ability of E2020 to improve performance in these cognitive tasks resembles the profile of other cholinesterase inhibitors, including tacrine, that also improve cognitive function in Alzheimer's disease patients. Because of its more favourable clinical safety profile, E2020 may provide a significantly improved palliative therapy for dementia.
Rupniak
N M
NM
Merck Sharp & Dohme Neuroscience Research Centre, Harlow, Essex, UK.
Tye
S J
SJ
Field
M J
MJ
D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D000077265:Donepezil; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000109:Acetylcholine