Inhibition of Acetylcholinesterase Modulates the Autoregulation of Cerebral Blood Flow and Attenuates Ischemic Brain Metabolism in Hypertensive Rats

Sadoshima, Seizo; Ibayashi, Setsuro; Fujii, Kenichi; Nagao, Tetsuhiko; Sugimori, Hiroshi; Fujishima, Masatoshi

doi:10.1038/jcbfm.1995.105

Cited by 38 publications

(22 citation statements)

References 34 publications

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“…In animal models, ChE-Is induce vascular relaxation and improve CBF in the ischaemic brain (Sadoshima et al, 1995 ;Tanaka et al, 1994Tanaka et al, , 1995Tsujimoto et al, 1993). Furthermore, treatment with ChE-Is may prevent cholinergic deficits and reduce pyramidal cell loss in ischaemic hippocampus (Tanaka et al, 1994(Tanaka et al, , 1995.…”

Section: Cholinergic Neurotransmission and Rcbfmentioning

confidence: 98%

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Lane

Potkin

Enz

2005

Int. J. Neuropsychopharm.

533

331

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The cholinesterase inhibitors (ChE-Is) attenuate the cholinergic deficit underlying the cognitive and neuropsychiatric dysfunctions in patients with AD. Inhibition of brain acetylcholinesterase (AChE) has been the major therapeutic target of ChE-I treatment strategies for Alzheimer's disease (AD). AChE-positive neurons project diffusely to the cortex, modulating cortical processing and responses to new and relevant stimuli. Butyrylcholinesterase (BuChE)-positive neurons project specifically to the frontal cortex, and may have roles in attention, executive function, emotional memory and behaviour. Furthermore, BuChE activity progressively increases as the severity of dementia advances, while AChE activity declines. Therefore, inhibition of BuChE may provide additional benefits. The two cholinesterase (ChE) enzymes that metabolize acetylcholine (ACh) differ significantly in substrate specificity, enzyme kinetics, expression and activity in different brain regions, and complexity of gene regulation. In addition, recent evidence suggests that AChE and BuChE may have roles beyond 'classical' co-regulatory esterase functions in terminating ACh-mediated neurotransmission. 'Non-classical' roles in modulating the activity of other proteins, regional cerebral blood flow, tau phosphorylation, and the amyloid cascade may affect rates of AD progression. If these additional mechanisms are demonstrated to underlie clinically meaningful effects, modification of the over-simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment, ignoring the potential of cholinergic therapies to modify the disease process, may be appropriate. The specificity of ChE inhibitory activity, up-regulation of AChE activity and changes in the composition of AChE molecular forms over time, selectivity for AD-relevant ChE molecular forms, brain vs. peripheral selectivity, and pharmacokinetic profile may be important determinants of the acute and long-term efficacy, safety and tolerability profiles of the different ChE-Is. This review focuses on new evidence for the roles of BuChE and AChE in symptom generation and rate of underlying disease progression in dementia, and argues that it may be appropriate to re-evaluate the place of ChE-Is in the treatment of dementia.

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Section: Cholinergic Neurotransmission and Rcbfmentioning

confidence: 98%

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Lane

Potkin

Enz

2005

Int. J. Neuropsychopharm.

533

331

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“…Animal models suggest that sustained cholinesterase inhibition may have a role in the treatment of ischemiainduced neurodegenerative disease [56][57][58][59]. Treatment with rivastigmine mitigated cholinergic deficits, reduced pyramidal loss, and attenuated the increase in activated glia in the ischemic hippocampus [56,57].…”

Section: Subcortical Ischemia and Cerebrovascular Lesionsmentioning

confidence: 99%

Executive Dyscontrol in Dementia, with Emphasis on Subcortical Pathology and the Role of Butyrylcholinesterase

Bullock¹,

Lane

2007

CAR

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Executive functions describe a variety of cognitive processes responsible for structuring behaviors around goals, and developing plans to achieve those goals in relation to the environment. In addition to deficits in basal forebrain cholinergic neuronal input into the frontal cortex, impaired control of executive function has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. In addition to executive dysfunction, features that imply fronto-subcortical pathology include profound slowing of cognition, attentional deficits, apathy and changes in mood. Fronto-subcortical systems are vulnerable to white matter change, atrophy, and certain forms of neurotransmitter depletion. The diffuse, and likely non-cholinergic, projections of acetylcholinesterase (AChE)-containing thalamic neurons innervate all cortical areas. Butyrylcholinesterase (BuChE) activity is relatively high in thalamic nuclei that project to frontal cortical structures involved in attention, executive function, and behavior. However, the largest pool of BuChE in the brain is found in the glia, particularly those in deeper cortical and subcortical structures. These findings suggest that BuChE may also be an important therapeutic target in the management of symptoms due to subcortical pathology. Whereas 'pure' Alzheimer's disease (AD) may involve significant subcortical pathology in addition to cortical pathology, AD with cerebrovascular disease, vascular dementia (VaD), Parkinson's disease dementia (PDD) and dementia due to Lewy bodies (DLB) may involve a generally greater degree of subcortical, in addition to cortical, pathology. It may be hypothesized that these dementia types, which are characterized by executive dysfunction, might derive particular benefits from cholinesterase inhibitors such as rivastigmine that inhibit BuChE in addition to AChE.

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“…Another possible explanation for the increase in effect on cognition in patients with AD observed with rivastigmine therapy may be the ability of the agent to increase cerebral blood flow. [25][26][27] It has been suggested that decreased cerebral blood flow may precede and or contribute to neuronal degeneration in AD.…”

Section: Commentmentioning

confidence: 99%

Analysis of Outcome in Retrieved Dropout Patients in a Rivastigmine vs Placebo, 26-Week, Alzheimer Disease Trial

Farlow¹,

Potkin²,

Koumaras³

et al. 2003

Arch Neurol

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Background: Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease (AD). In studies designed with a washout period at the end of the study, after treatment with a cholinesterase inhibitor is discontinued, the cognitive benefits of therapy are no longer apparent following washout. The rivastigmine trials discussed in this article were not designed with a posttreatment washout period at the end of the study. Therefore, to evaluate the effect of discontinuing treatment, we analyzed the retrieved dropout (RDO) population. Objective: To evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine. Design and Methods: Eligible patients with AD (Mini-Mental State Examination [MMSE] score, 10-26, inclusive) were enrolled in 1 of three 26-week, double-blind, placebo-controlled studies (Novartis US Pivotal [doserange] Trial , US fixed-dose study, and a Global Pivotal [dose-range] Trial) that compared rivastigmine therapy with placebo. Patients who discontinued study participation (for any reason) (considered to be the RDO population) were encouraged to return for their scheduled week 26 efficacy evaluations. Effects on cognition were assessed using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Results: The results for the Novartis US Pivotal Trials and for the 3 studies combined (Novartis studies B352,

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Inhibition of Acetylcholinesterase Modulates the Autoregulation of Cerebral Blood Flow and Attenuates Ischemic Brain Metabolism in Hypertensive Rats

Cited by 38 publications

References 34 publications

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Targeting acetylcholinesterase and butyrylcholinesterase in dementia

Executive Dyscontrol in Dementia, with Emphasis on Subcortical Pathology and the Role of Butyrylcholinesterase

Analysis of Outcome in Retrieved Dropout Patients in a Rivastigmine vs Placebo, 26-Week, Alzheimer Disease Trial

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