Study of neuroprotection of donepezil, a therapy for Alzheimer's disease

Akasofu, Shigeru; Kimura, M.; Kosasa, Takashi; Sawada, Kohei; Ogura, Hiroo

doi:10.1016/j.cbi.2008.04.045

Cited by 79 publications

(47 citation statements)

References 20 publications

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“…Current neuroprotective treatment options cover all of the molecular targets of the dementia cascades. Interestingly, protective effects of cholinergic agents, especially AChE inhibitors, involve multiple mechanisms (I [48,[127][128][129] ; II [130][131][132] ; III [85,98] ; IV [127,133] ; V [90,133,134] ; references to literature regarding VI and VII can be found throughout this review). Abbreviations: ATP, adenosine triphosphate; CaM, calmodulin; Hup A, huperzine A; JAK/STAT, Janus kinase/signal transducer and activator of transcription; MMP, matrix metalloproteinase; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; PAF, platelet activating factor.…”

Section: Cholinergic Deficiency In Vad Animal Models and Vad Patientsmentioning

confidence: 99%

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

2009

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Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.

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Section: Cholinergic Deficiency In Vad Animal Models and Vad Patientsmentioning

confidence: 99%

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

2009

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“…Donepezil, a potent AChE inhibitor that is used for the treatment of AD, shows neuroprotective effects against A␤ 42 toxicity in cultured rat septal cholinergic neurons [270]. Donepezil also decreases neuronal damage in cultured neurons after NMDA treatment [271]. The level of NR1 on the cell surface and glutamate mediated Ca 2+ entry is reduced by donepezil, which might contribute to its neuroprotective effects [272].…”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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“…The non-neuronal cholinergic system might also be involved in efficient glucose metabolism in cardiomyocytes. Additionally, a number of experimental studies strongly suggest that donepezil directly affect cells via a mechanism that is independent of its pharmacological action of acetylcholinesterase inhibition [19,[47][48][49]. Further investigation is needed to determine the molecular mechanism of the donepezil-induced increase in the efficiency of cardiac glucose utilization.…”

Section: Discussionmentioning

confidence: 99%