title: Investigation into the efficacy of the acetylcholinesterase inhibitor, donepezil, and novel procognitive agents to induce gamma oscillations in rat hippocampal slices.
abstract: One of the major neuropathological hallmarks in Alzheimer's disease (AD) is the loss of cholinergic neurones of the nucleus basalis of Meynert (NbM). This consistent finding gave rise to the 'cholinergic' hypothesis of AD and lead to the subsequent development of acetylcholinesterase (AChE) inhibitors; the first class of drug to be approved for the treatment of AD. However, several studies have questioned the efficacy of using AChE inhibitors in AD. In this study we have investigated the ability of two AChE inhibitors, donepezil (Aricept) and physostigmine, to induce gamma oscillatory activity in rat hippocampal slices; network activity believed to play a role in higher cognitive function. We report here that donepezil is capable of inducing gamma oscillations in region CA3 of rat hippocampal slices, which may contribute to its procognitive action. However, donepezil-induced gamma oscillations are weak in comparison to physostigmine. We also explore the activity of novel agents with known procognitive activity, and show that one such agent, the M(1) muscarinic acetylcholine receptor agonist, 77-LH-28-1, can significantly enhance donepezil-induced gamma oscillations. These data support the notion that it should be possible to find a more efficacious AChE inhibitor or an adjunctive approach, to provide a better therapeutic intervention in AD.
authors.affiliation: Synaptic Plasticity and Neural Network Dynamics Discovery Performance Unit, Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK. jonathan.spencer@gmx.com
authors.forename: J P
authors.initials: JP
authors.lastname: Spencer
authors.forename: L J
authors.initials: LJ
authors.lastname: Middleton
authors.forename: C H
authors.initials: CH
authors.lastname: Davies
mesh_terms: D000818:Animals; D058256:Brain Waves / Q000187:drug effects* / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007189:Indans / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D051381:Rats
chemical_list: C531940:77-LH-28-1; D002800:Cholinesterase Inhibitors; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D015363:Quinolones; D000077265:Donepezil