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Non-Cholinergic Strategies for Treating and Preventing Alzheimer's Disease
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Non-Cholinergic Strategies for Treating and Preventing Alzheimer's Disease
作者:
P. Murali Doraiswamy,
期刊:
CNS Drugs
(ADIS Available online 2002)
卷期:
Volume 16,
issue 12
页码: 811-824
ISSN:1172-7047
年代: 2002
出版商: ADIS
关键词: Alzheimer's disease;Antidementias, therapeutic use;Antioxidants, therapeutic use;Chelating agents, therapeutic use;Estrogens, therapeutic use;FPF 1070, therapeutic use;Ginkgo biloba leaf extract, therapeutic use;HMG CoA reductase inhibitors, therapeutic u
数据来源: ADIS
摘要:
The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective β-amyloid (Aβ) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed.Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g.Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor−based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], γ-aminobutyric acid [GABA],N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors).Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results withGinkgo bilobahave been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia.This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.
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