Effect of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate, a novel acetylcholinesterase inhibitor, on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats

Xu, Ajing; Chen, Zhong; Yanai, Kazuhiko; Huang, Yu; Wei, Er Qing

doi:10.1016/s0304-3940(02)00830-3

Cited by 15 publications

(9 citation statements)

References 14 publications

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“…Similar protection was not found for other cholinesterase inhibitors, with the exception of huperzine A. Similarly, in an in vivo rodent model of transient ischemia, pretreatment with donepezil was associated with diminution of cognitive effects and reduction of hippocampal cell loss [42] . In studies of skin microvasculature, donepezil was found to reduce the vasoconstrictive effects of A β peptides [43] .…”

Section: Donepezil Improves Cerebral Blood Fl Ow and Activity-fl Ow Csupporting

confidence: 55%

Donepezil: potential neuroprotective and disease-modifying effects

Jacobson

Sabbagh

2008

Expert Opinion on Drug Metabolism & Toxicology

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Background : There is substantial evidence from preclinical studies that cholinesterase inhibitors affect basic processes that have been implicated in Alzheimer's disease (AD) pathogenesis, suggesting that these drugs should have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil, which is the focus of this review. Objective : To summarize the preclinical literature regarding the effects of donepezil on cellular and molecular processes underlying AD. Second, to suggest reasons for the apparent disparity between robust preclinical effects and modest clinical effects of this drug and others in its class. Methods : Articles retrieved from PubMed searches were critically reviewed and selected for relevance to the current topic. Results/conclusion : Donepezil has numerous cellular and molecular effects that should influence AD progression.

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Section: Donepezil Improves Cerebral Blood Fl Ow and Activity-fl Ow Csupporting

confidence: 55%

Donepezil: potential neuroprotective and disease-modifying effects

Jacobson

Sabbagh

2008

Expert Opinion on Drug Metabolism & Toxicology

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“…, 2001). The possible significance of this effect has been further demonstrated in a study in rats, which found that donepezil protected against loss of spatial memory caused by chronic ischaemia (Xu et al. , 2002).…”

Section: Clinical Trials Of Donepezil In Vad and Ad + Cvdmentioning

confidence: 94%

“…Donepezil has been found to protect cultured PC12 cells (neurone-like cells) from deprivation of oxygen and glucose, a model for ischaemia (Zhou et al, 2001). The possible significance of this effect has been further demonstrated in a study in rats, which found that donepezil protected against loss of spatial memory caused by chronic ischaemia (Xu et al, 2002). It remains to be determined whether these effects are due to inhibition of acetylcholinesterase or represent a benefit from an as yet unknown activity of donepezil.…”

Section: Clinical Trials Of Donepezil In Vad and Ad + Cvdmentioning

confidence: 99%

Dementia with cerebrovascular disease: the benefits of early treatment

Schindler

2005

Euro J of Neurology

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Patients with vascular dementia (VaD) and Alzheimer's disease with cerebrovascular disease (AD + CVD) have dementia associated with underlying CVD. Although diagnosis of VaD is challenging, VaD is typically characterized by a stepwise progression of dementia that is closely associated with stroke and focal neurological findings, and a symptom profile that often includes executive dysfunction leading to decreased ability to perform instrumental activities of daily living (IADL). In contrast, AD + CVD patients typically present with progressive deterioration of cognition/memory that may also be influenced by concurrent cerebrovascular events. Early diagnosis and intervention are desirable to prevent further decline due to subsequent vascular events. Management of CVD can limit deterioration of cognitive symptoms in VaD patients, and treatment benefits with cholinesterase inhibitors may be realized as improvement above baseline levels in dementia symptoms. Results from a combined analysis of two 24-week, placebo-controlled clinical trials show that donepezil-treated VaD patients improve in cognition, global function, and performance of IADL. In contrast, AD + CVD patients may continue to decline despite management of CVD, and treatment benefits should be recognized as initial improvements followed by stabilization or slowed decline of dementia symptoms over time. In post-marketing studies, donepezil-treated AD and AD + CVD patients show similar benefits in cognition, global function, and quality of life. The results of these studies support the use of donepezil in treatment of patients with VaD or AD + CVD.

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“…Additionally, TAK‐147 has been shown to inhibit moderately muscarinic M1 and M2 receptor binding, but with very weak or no inhibition of high‐affinity choline ([2‐hydroxyethyl] trimethylammonium) uptake or binding to nicotinic receptor (Hirai et al ., 1997). Moreover, TAK‐147 increases cerebral energy metabolism (Nakayama et al ., 1996; Ishihara et al ., 2000), improves hippocampal metabolic activity (Xu et al ., 2002) and, like E2020, enhances the choline acetyltransferase activity more potently than tacrine (Kato et al ., 1999). Furthermore, TAK‐147, at AChE inhibiting dose, is reported to provide NGF‐like neurotrophic activity on central cholinergic neurons not only via AChE inhibition but also possibly via an effect on tau receptors (Kato et al ., 1999; Ishihara et al ., 2000).…”

Section: Introductionmentioning

confidence: 99%

Effect of oral administration of zanapezil (TAK‐147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

Hatip‐Al‐Khatib

Iwasaki

Yoshimitsu

et al. 2005

British J Pharmacology

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1 Zanapezil -1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl) propan-1-one fumarate)) is a selective acetylcholine (ACh) esterase inhibitor under investigation as a drug for Alzheimer's disease (AD) treatment. 2 In this study, the effects of TAK-147 at 2 mg kg À1 p.o. for 21 days, compared to donepezil (E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis-high-performance liquid chromatography. 4 On the 21st day and prior to the last dose, TAK-147 increased ACh, Epi, DA and 5-HT, whereas E2020 increased MHPG, Epi and DA. Following the last dose, TAK-147 increased NE, whereas E2020 increased NE, ACh and 5-HT in addition to their effects prior to the last dose. TAK-147 decreased HVA : DA ratio, but only marginally decreased DOPAC : DA and 5-HIAA : 5-HT ratios. On the other hand, E2020 decreased ratios of HVA : DA, DOPAC : DA (prior to the last dose), and 5-HIAA : 5-HT (90-180 min after the last dose). Both drugs decreased MHPG : NE only at 180 min after the last dose. The results also showed that TAK-147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas E2020 increased the ratio only before the last dose. The present results show that TAK-147 at a subthreshold dose could differentially increase ACh and 5-HT, compared to MHPG increased by E2020. The last dose of each drug could extend their effects to other monoamines. 5 The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort neurological disorders depending on the type of the monoamine underlying the disorder.

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Effect of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate, a novel acetylcholinesterase inhibitor, on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats

Cited by 15 publications

References 14 publications

Donepezil: potential neuroprotective and disease-modifying effects

Donepezil: potential neuroprotective and disease-modifying effects

Dementia with cerebrovascular disease: the benefits of early treatment

Effect of oral administration of zanapezil (TAK‐147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

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