Clinical Profile of Donepezil in the Treatment of Alzheimer’s Disease

Doody, Rachelle S.

doi:10.1159/000052761

Cited by 62 publications

(33 citation statements)

References 56 publications

(51 reference statements)

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“…Thus, mangiferin improved long-term memory in scopolamine-induced amnestic mouse models by inhibiting AChE, like AChE inhibitors previously reported. 3,11) Mangiferin may reverse deficits in hippocampal long-term memory via cholinergic enhancement.…”

Section: Mangiferin Increases Acetylcholine Level Reduced By Scopolammentioning

confidence: 99%

Mangiferin Ameliorates Scopolamine-Induced Learning Deficits in Mice

Jung

Lee

Han

et al. 2009

Biological & Pharmaceutical Bulletin

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Section: Mangiferin Increases Acetylcholine Level Reduced By Scopolammentioning

confidence: 99%

Mangiferin Ameliorates Scopolamine-Induced Learning Deficits in Mice

Jung

Lee

Han

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Clinical trials revealed that donepezil (Aricept, previously E2020, Pfizer), a selective noncompetitive inhibitor of acetylcholinesterase (AChE; see Sugimoto et al (2002) for a review), had cognitive benefits in Alzheimer's disease patients afflicted with mild to moderate degrees of dementia (Mintzer and Kershaw, 2003). Presently donepezil is used to treat cognitive deficits associated with Alzheimer's disease (Rogers and Friedhoff, 1998;Doody, 1999;Grutzendler and Morris, 2001). Additionally, this drug has been found to reverse memory deficits in variety of rodent models of learning and memory.…”

Section: Introductionmentioning

confidence: 99%

Combination of Rimonabant and Donepezil Prolongs Spatial Memory Duration

Wise

Iredale

Stokes

et al. 2007

Neuropsychopharmacol

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The observations that the cannabinoid 1 (CB 1 ) receptor antagonist/inverse agonist, rimonabant, and the selective noncompetitive inhibitor of acetylcholinesterase (AChE), donepezil, improve performance in a variety of animal memory models, suggest that these neurochemical systems play integral roles in cognition. The present study tested whether each of these agents administered alone or in combination will prolong the duration of spatial memory. Rats were trained in a two-phase radial-arm maze procedure, consisting of acquisition and retrieval tests, which were separated by an 18 h delay. Each drug was administered 30 min before the acquisition phase, immediately after the acquisition phase, or 30 min before the retrieval test to assess acquisition/consolidation, consolidation, and retrieval mnemonic processes, respectively. Rimonabant or donepezil administered before the acquisition phase, but not immediately after acquisition or before retrieval, led to a significant decrease in the number of errors committed during the retrieval test. Combined administration of subthreshold doses of rimonabant and donepezil that had no discernable effects on performance when given alone, enhanced memory.These results taken together demonstrate that the delay radial-arm maze task is sufficiently sensitive to detect memory enhancing effects of these drugs. Moreover, these findings suggest that combined administration of subthreshold doses of rimonabant and donepezil can improve memory and may represent a novel approach to treat cognitive deficits associated with neurodegenerative disorders.

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“…Cholinesterase inhibitors were the first generation of such candidate therapeutics (11)(12)(13)(14)(15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques.…”

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confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

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Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

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Clinical Profile of Donepezil in the Treatment of Alzheimer’s Disease

Cited by 62 publications

References 56 publications

Mangiferin Ameliorates Scopolamine-Induced Learning Deficits in Mice

Mangiferin Ameliorates Scopolamine-Induced Learning Deficits in Mice

Combination of Rimonabant and Donepezil Prolongs Spatial Memory Duration

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

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