The Cholinergic Hypothesis of Geriatric Memory Dysfunction

Bartus, Raymond T.; Dean, Reginald L.; Beer, Bernard; Lippa, Arnold S.

doi:10.1126/science.7046051

Cited by 5,230 publications

(2,300 citation statements)

References 137 publications

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“…A number of studies have demonstrated that vestibular stimulation can improve cognition in humans (reviewed in [91][92][93]). Given that synaptic plasticity is altered in patients with Alzheimer's disease [94] and degeneration of basal forebrain cholinergic neurons is a pathological hallmark of this disease [14,15,95,96], vestibular stimulation may provide a novel treatment to improve hippocampus-dependent cognitive deficits in affected patients.…”

Section: Resultsmentioning

confidence: 99%

“…Selective ablation of septal cholinergic neurons by intraseptal microinjection of the immunotoxin 192 immunoglobulin G-saporin (192 IgG-saporin) caused spatial learning and memory impairments in some [8][9][10] but not all experiments [11][12][13]. The cholinergic hypothesis of Alzheimer's disease postulates that degeneration of cholinergic neurons in the basal forebrain including the MS contributes to the cognitive deficits of Alzheimer's disease [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

Tai

Leung

2012

Behavioural Brain Research

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

Tai

Leung

2012

Behavioural Brain Research

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“…That stimulation of the cholinergic system improves cognitive processes has long been observed (Deutsch 1971;Bartus et al 1982;Coyle 1995). Conversely, blockade of the cholinergic system disrupts memory functions.…”

Section: Discussionmentioning

confidence: 95%

“…Microdialysis studies have shown that DM235 increases ACh release from the rat parietal cortex (Manetti et al 2000b), a cerebral structure involved in the modula- tion of cognitive processes (Bartus et al 1982). Therefore, the potentiation of the cholinergic system by DM235 could make it able to prevent amnesia induced by an antimuscarinic drug as well as by the administration of a nicotinic antagonist.…”

Section: Discussionmentioning

confidence: 99%

DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer

Ghelardini

Galeotti

Gualtieri

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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DM235 (sunifiram), a new compound structurally related to piracetam, prevented the amnesia induced by scopolamine (1.5 mg kg -1 i.p.), after intraperitoneal (0.001-0.1 mg kg -1 ) or oral (0.01-0.1 mg kg -1 ) administration, as shown by a passive avoidance test in mice. The antiamnesic effect of DM235 was comparable to that of well-known nootropic drugs such as piracetam (30-100 mg kg -1 i.p.), aniracetam (100 mg kg -1 p.o.) or rolipram (30 mg kg -1 p.o.). DM235 also prevented mecamylamine (20 mg kg -1 i.p.)-, baclofen (2 mg kg -1 i.p.)-and clonidine (0.125 mg kg -1 i.p.)-induced amnesia in the same test. In the Morris water maze test with rats, scopolamine (0.8 mg kg -1 i.p.) inhibited the reduction of escape latency in both acquisition and retention/retraining tests. DM235 (0.1 mg kg -1 i.p.), 20 min before each daily acquisition training, prevented the scopolamine-induced memory impairment. DM235 (1 mg kg -1 i.p.) also reduced the duration of pentobarbitone-induced hypnosis in mice without modifying the induction time of hypnosis. At the highest effective doses, the investigated compound neither impaired motor coordination (rota-rod test), nor modified spontaneous motility and inspection activity (Animex and hole board tests).These results indicate that DM235, a compound structurally related to piracetam, is a novel nootropic endowed with the capability to prevent cognitive deficits at very low doses. Indeed, its potency is about 1,000 times higher than that of the most active piracetam-like compounds.

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“…Lesioning of the NBM causes a decline of cholinergic projections, mimicking the characteristic loss of forebrain cholinergic innervation in AD (Bartus et al, 1982;Gaykema et al, 1992).…”

Section: Introductionmentioning

confidence: 93%

Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

et al. 2010

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Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Granic, I., Nyakas, C., Luiten, P. G. M., Eisel, U. L. M., Halmy, L. G., Gross, G., ... Nimmrich, V. (2010). Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats. Neuropharmacology, 59(4-5), 334-342. DOI: 10.1016334-342. DOI: 10. /j.neuropharm.2010 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. s t r a c tAmyloid-b (Ab) is toxic to neurons and such toxicity is e at least in part e mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. The present study reveals that inhibition of calpain is also neuroprotective in an in vivo model of Ab oligomer-induced neurodegeneration in rats. Ab-induced lesions of the nucleus basalis induced a significant decrease in the number of cholinergic neurons and their projecting fibers, as determined by analysis of choline-acetyltransferase in the nucleus basalis magnocellularis and cortical mantle of the lesioned animals. Treatment with the calpain inhibitor A-705253 significantly attenuated cholinergic neurodegeneration in a dose-dependent manner. Calpain inhibition also significantly diminished the accompanying neuroinflammatory response, as determined by immunohistochemical analysis of microglia activation. Administration of b-amyloid markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dose-dependently prevented this behavioral deficit.In order to determine whether pre-treatment with the calpain inhibitor is necessary to exhibit its full protective effect on neurons we induced Ab toxicity in primary neuronal cultures and administered A-705253 at various time points before and after Ab oligomer application. Although the protective effect was higher when A-705253 was applied before induction of Ab toxicity, calpain inhibition was still beneficial when applied up to 1 h post-treatment.We conclude that inhibition of calpains may represent a valuable strategy for the prevention of Ab oligomer-induced neuronal decline and associated cognitive deterioration.

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The Cholinergic Hypothesis of Geriatric Memory Dysfunction

Cited by 5,230 publications

References 137 publications

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer

Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

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