Acetylcholinesterase Inhibitors for the Treatment of Wernicke–korsakoff Syndrome−three Further Cases Show Response to Donepezil

Cochrane, Murray; Cochrane, Ashley; Jauhar, Pramod; Ashton, Elizabeth

doi:10.1093/alcalc/agh127

Cited by 40 publications

(27 citation statements)

References 14 publications

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“…Furthermore, our recent data demonstrated that when the hippocampal ACh levels are increased in the hippocampus by direct application of physostigmine, the behavioral impairment in spontaneous alternation in PTD rats is eliminated (unpublished data). Limited clinical trails have also revealed that anticholinesterase inhibitors improve cognitive functioning in patients with WKS [3,9]. Thus, although cholinergic dysfunction may be an over looked feature in thiamine deficiency-induced amnesia, increasing ACh levels does lead to significant behavioral recovery in the human disorder of WKS and the PTD model.…”

Section: Discussionmentioning

confidence: 99%

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

2007

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A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate diencephalic-limbic interactions. In-vivo acetylcholine (ACh) efflux, a marker of memory-related activation, was measured in the hippocampus and the amygdala of PTD-treated and pair-fed (PF) control rats while they were tested on a spontaneous alternation task. During behavioral testing, all animals displayed increases in ACh efflux in both the hippocampus and amygdala. However, during spontaneous alternation testing ACh efflux in the hippocampus and the alternation scores were higher in PF rats relative to PTD-treated rats. In contrast, ACh efflux in the amygdala was not suppressed in PTD treated rats, relative to PF rats, prior to or during behavioral testing. In addition, unbiased stereological estimates of the number of choline acetyltransferase (ChAT) immunopositive neurons in the medial septal/diagonal band (MS/DB) and nucleus basalis of Meynert (NBM) also reveal a selective cholinergic dysfunction: In PTD-treated rats a significant loss of ChAT-immunopositive cells was found only in the MS/DB, but not in the NBM. Significantly, these results demonstrate that thiamine deficiency causes selective cholinergic dysfunction in the septohippocampal pathway. Keywords diencephalon; hippocampus; amygdala; microdialysis; acetylcholine; stereology Selective septohippocampal-but not forebrain amygdalarcholinergic dysfunction in diencephalic amnesiaDiencephalic lesions are seen in a range of disorders: malnourishment, ischemic infarcts, viral infections, tumors and traumatic damage. Damage to certain nuclei and fiber systems within the diencephalon interrupts the flow of information between key memory structures and thus causes severe and long-lasting amnesia [25,29,45]. Although there is evidence that lesions to particular diencephalic nuclei result in memory impairment in their own right, there is also evidence that damage to diencephalic nuclei can disrupt memory circuits leading to dysfunction in other regions of the brain [4,29,45,49,53].Corresponding author: Lisa M. Savage, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, 13902, e-mail: lsavage@binghamton.edu, fax: 607-777-4890. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. At one point, WKS patients were labeled as "temporal lobe-related amnesiacs" based on their memory performance [10]. This clinical population was critical for the development of the memory system classifications (i.e., declarative vs. nondeclarative memory [51]). However, it is clear from...

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Section: Discussionmentioning

confidence: 99%

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

2007

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“…AChE inhibitors (AChEIs) have also been suggested for other possible therapeutic applications, i.e. Wernicke-Korsakoff syndrome 10 and posttraumatic cognitive impairments 11 . Furthermore, besides of its cholinergic role, in the AD the AChE plays a non-cholinergic role accelerating beta-amyloid plaques assembly 12 .…”

Section: Introductionmentioning

confidence: 99%

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Vita

Pandolfi

Ornano

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.

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“…Furthermore, chronic physostigmine administration in rats exposed to TD has been shown to reverse the impairment on an avoidance-learning task if started at an early phase of treatment (Nakagawasai et al, 2000). A limited number of case studies have revealed that WKS patients show improved cognitive abilities when given acetylcholinesterase inhibitors (Angunawela & Barker, 2001;Cochrane, Cochrane, Jauhar, & Ashton, 2005). These neurochemical as well as pharmacological data point towards the cholinergic system being involved in the learning and memory problems associated with thiamine deficiency and more generally diencephalic amnesia.…”

Section: Introductionmentioning

confidence: 99%

Blunted hippocampal, but not striatal, acetylcholine efflux parallels learning impairment in diencephalic-lesioned rats

Roland

Savage

2007

Neurobiology of Learning and Memory

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A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate the dynamic role of hippocampal and striatal acetylcholine (ACh) efflux across acquisition of a nonmatching-to-position (NMTP) T-maze task. Changes in ACh efflux were measured in rats at different time points in the acquisition curve of the task (early= day 1, middle = day 5, and late = day 10). Overall, the control group had higher accuracy scores than the PTD group in the latter sessions of NMTP training. During the three microdialysis sampling points, all animals displayed significant increases in ACh efflux in both hippocampus and striatum, while performing the task. However, on day 10, the PTD group showed a significant behavioral impairment that paralleled their blunted hippocampal-but not striatal-ACh efflux during maze training. The results support selective diencephalic-hippocampal dysfunction in the PTD model. This diencephalichippocampal interaction appears to be critical for successful episodic and spatial learning/memory.

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Acetylcholinesterase Inhibitors for the Treatment of Wernicke–korsakoff Syndrome−three Further Cases Show Response to Donepezil

Cited by 40 publications

References 14 publications

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Blunted hippocampal, but not striatal, acetylcholine efflux parallels learning impairment in diencephalic-lesioned rats

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