The Pharmacological Basis for Metrifonate’s Favourable Tolerability in the Treatment of Alzheimer’s Disease

Schmidt, Bernard; Heinig, Roland

doi:10.1159/000051194

Cited by 10 publications

(2 citation statements)

References 26 publications

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“…This hypothesis claims attention to the short-and long-term effects of AChE inhibition, that we addressed using as Molecular Psychiatry reference molecule the prodrug metrifonate (MTF) and its active metabolite dichlorvos (DDVP), a compound that has demonstrated clinical efficacy toward cognitive and behavioural functions in patients with Alzheimer's disease. 23,24 In our investigation we have observed that the shortterm treatment with metrifonate or its active product dichlorvos can affect APP metabolism by increasing the rate of ␣-secretase processing, resulting in the stimulation of sAPP␣ release from SH-SY5Y neuroblastoma cells. The treatment with DDVP elicited a maximal increase of sAPP␣ secretion at a concentration Figure 6 Expression of AChE following prolonged treatment with MTF.…”

Section: Discussionmentioning

confidence: 87%

Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein

et al. 2001

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We have investigated the acute and chronic effect of metrifonate (MTF) and dichlorvos (DDVP), respectively the prodrug and active acetylcholinesterase inhibitor, on the secretory processing of the amyloid precursor protein (APP) in SH-SY5Y neuroblastoma cells. We demonstrate that the acute treatment of SH-SY5Y cells with both compounds results in an increased secretion of the soluble fragment of APP (sAPP␣) into the conditioned media of cells, with a pattern correlated to the level of acetycholinesterase inhibition. The regulation of APP processing in these conditions is mediated by an indirect cholinergic effect on muscarinic receptors, as demonstrated by inhibition with atropine. We have also followed APP expression and metabolism after long-term treatment with metrifonate. Treated cells showed reduced AChE activity after 24, 48 h and also following 7 days of repeated treatment, a time point at which increased AChE expression was detectable. At all time points sAPP␣ release was unaffected suggesting that enhanced sAPP␣ release by MTF is transitory, nevertheless the sensitivity of cholinergic receptors was unchanged, as indicated by the fact that cholinergic response can be elicited similarly in untreated and treated cells. APP gene expression was unaffected by long-term AChE inhibition suggesting that increased short-term sAPP␣ release does not elicit compensatory effects. Molecular Psychiatry (2001) 6, 520-528.

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Section: Discussionmentioning

confidence: 87%

Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein

et al. 2001

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“…Metrifonate has now undergone phase II and phase III trials, and a New Drug Application (NDA) was submitted to the United States Food and Drug Administration (FDA). Previous reviews have addressed aspects of its pharmacology and acute tolerability in early clinical trials (11,12,46).…”

Section: Introductionmentioning

confidence: 99%

Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Schneider

Giacobini

1999

CNS Drug Reviews

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Medicinal chemistry approaches for the treatment and prevention of Alzheimer's disease

Бачурин

2002

Medicinal Research Reviews

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Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites.

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The Pharmacological Basis for Metrifonate’s Favourable Tolerability in the Treatment of Alzheimer’s Disease

Cited by 10 publications

References 26 publications

Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein

Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein

Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Medicinal chemistry approaches for the treatment and prevention of Alzheimer's disease

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