Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

详细信息    查看全文

• 作者：Jos茅-Carlos Fern谩ndez-Morales ; Juan-Alberto Arranz-Tagarro ; Enrique Calvo-Gallardo ; Marcos Maroto ; Juan-Fernando Pad铆n ; Antonio G. Garc铆a
• 刊名：ACS Chemical Neuroscience
• 出版年：2012
• 出版时间：November 21, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：873-883
• 全文大小：367K
• 年卷期：v.3,no.11(November 21, 2012)
• ISSN：1948-7193

文摘

For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (A尾), to prevent A尾 deposition, or to clear up A尾 plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3尾). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca²⁺ channels (VDCCs) and on the mitochondrial Na⁺/Ca²⁺ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca²⁺ cycling (NCC) and futile mitochondrial Ca²⁺ cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca²⁺ homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca²⁺ entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca²⁺ efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.

Keywords:

cs.org/action/doSearch?action=search&searchText=Alzheimer%27s+disease&qsSearchArea=searchText">Alzheimer's disease; cs.org/action/doSearch?action=search&searchText=neuronal+calcium+cycling&qsSearchArea=searchText">neuronal calcium cycling; cs.org/action/doSearch?action=search&searchText=mitochondrial+calcium+cycling&qsSearchArea=searchText">mitochondrial calcium cycling; cs.org/action/doSearch?action=search&searchText=calcium+and+cell+death&qsSearchArea=searchText">calcium and cell death; cs.org/action/doSearch?action=search&searchText=L%5C-type+calcium+channel&qsSearchArea=searchText">L-type calcium channel; cs.org/action/doSearch?action=search&searchText=mitochondrial+sodium%E2%88%92calcium+exchanger&qsSearchArea=searchText">mitochondrial sodium鈭抍alcium exchanger; cs.org/action/doSearch?action=search&searchText=functional+tetrad&qsSearchArea=searchText">functional tetrad; cs.org/action/doSearch?action=search&searchText=multitarget+compounds&qsSearchArea=searchText">multitarget compounds; cs.org/action/doSearch?action=search&searchText=neurotoxicity&qsSearchArea=searchText">neurotoxicity; cs.org/action/doSearch?action=search&searchText=neuroprotection&qsSearchArea=searchText">neuroprotection