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Natural Product for the Treatment of Alzheimer's Disease

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Natural Product for the Treatment of Alzheimer's Disease J Basic Clin Physiol Pharmacol 2017; 28(5): 413–423 Review Thanh Tung Bui* and Thanh Hai Nguyen Natural product for the treatment of Alzheimer’s disease https://doi.org/10.1515/jbcpp-2016-0147 Received September 27, 2016; accepted May 28, 2017; previously Pathogenesis of Alzheimer’s disease published online July 14, 2017 Until now, the pathogenesis of AD is not yet completely Abstract: Alzheimer’s disease (AD) is related to increas- understood. The genetic susceptibility and environmental ing age. It is mainly characterized by progressive neu- factors are responsible for late onset sporadic AD, which rodegenerative disease, which damages memory and is the most common form of the disease. Many studies cognitive function. Natural products offer many options have attempted to understand the disease mechanism and to reduce the progress and symptoms of many kinds of develop a disease-modifying drug. Two main factors are diseases, including AD. Meanwhile, natural compound responsible for the development of AD: β-amyloid protein structures, including lignans, flavonoids, tannins, poly- and abnormal tau protein, or both of them. AD is charac- phenols, triterpenes, sterols, and alkaloids, have anti- teristized by the overproduction of β-amyloid proteins (Aβ) inflammatory, antioxidant, anti-amyloidogenic, and and hyperphosphorylated Tau protein, which can lead to anticholinesterase activities. In this review, we summa- the loss of synaptic connections and neurons in the hip- rize the pathogenesis and targets for treatment of AD. We pocampus and cerebral cortex, a decline in cognitive func- also present several medicinal plants and isolated com- tion, and dementia [2]. The accumulation of β-amyloid pounds that are used for preventing and reducing symp- protein and neurofibrillary tangles have been shown in toms of AD. AD patients. The overproduction and accumulation of Aβ lead to oxidation, lipid peroxidation, inflammation, dis- Keywords: acetylcholinesterase enzyme; Alzheimer’s turbance of cell functions, and apoptosis and formation of disease; β-amyloid; natural product. neurofibrillary tangles [3]. The tau protein is hyperphos- phorylated, which leads to the formation of tangles depos- ited in the hippocampus and, ultimately, to cell death [4]. Many biochemical changes within cells, such as oxidative Introduction stress, inflammation, metabolic disturbances, disruption of Ca2+ homeostasis, and the accumulation of unfolded/ Alzheimer’s disease (AD) is a disease related to aging. It mis-folded proteins, have been demonstrated to induce is neurodegenerative disease that leads to memory loss neuronal cell death in AD patients [5]. The two mecha- and impaired cognitive function. The reports of the World nisms involved in AD are oxidative damage and inflam- Health Organization in 2012 showed that over 35.6 million matory process, and both of these have been studied well people in the world have dementia, and about 60%–70% in the literature. of this population has AD. The same report also predicted that the number of people with dementia, and those with AD, shall continue to increase [1]. Acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease *Corresponding author: Thanh Tung Bui, School of Medicine and Cholinergic hypothesis is an important hypothesis that is Pharmacy, Vietnam National University, Hanoi, Office 506, Building used to explain the pathogenesis of AD. This hypothesis Y1, 144 XuanThuy, Cau Giay, Ha Noi, Vietnam, Tel.: +84-4-85876172, Fax: +84-0437450188, E-mail: [email protected] explains that AD is caused by a decrease in neurotrans- Thanh Hai Nguyen: School of Medicine and Pharmacy, Viet Nam mitter acetylcholine (Ach). Many drugs used in the treat- National University, Hanoi, Vietnam ment of AD are based on cholinergic hypothesis [6]. ACh, 414 Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease serotonin, and norepinephrine are neurotransmitter defi- stress in AD patients. Hence, antioxidant treatment is a cits in the brain that occur because of cell death. Many promising strategy for inhibiting disease progression. studies have shown that a low level of neurotransmitters A recent study has shown the link between antioxidant in a cholinergic system is responsible for cognitive decline intake and reduced symptoms of dementia [16]. Treatment and memory loss in AD patients [6–9]. Acetylcholinester- with antioxidants, such as those found n vitamin E, vitamin ase (AChE) is a main enzyme that degrades the ACh neu- C, selegiline, estrogen, and Ginkgo biloba, may inhibit the rotransmitter. Various therapeutic strategies elevate ACh development of AD [17]. Furthermore, some medicinal neurotransmitter levels, then increase cholinergic trans- plants with antioxidant activities also exhibit potential for mission by inhibiting ACh hydrolysis with AChE inhibitors, AD treatment. Jung et al. have reported that three major stimulating nicotinic and muscarinic receptors or using alkaloids in Coptidis rhizoma, including groenlandicine, cholinomimetic substances [9]. Drugs such as galantamine, berberine, and palmatine, can potentially exhibit anti-AD tacrine, donepezil, metrifonate or rivastigmine inhibit effects by inhibiting AChE activity and Aβ accumulation, AChE, augment the level of Ach, and improves cholinergic and also present antioxidant capacities to inhibit ROS and transmission. These drugs have been used to alleviate the RNS levels [13]. Silibinin, an isolated flavonoid from Silybum symptoms of AD, which are caused by the degeneration of marianum, also has an antioxidant property. Silibinin has cholinergic neurons and injured transmission. However, been shown to prevent memory impairment and oxidative the inhibition of AChE has not been very effective in the damage induced by Aβ in mice model, making it a poten- treatment of Alzheimer [9]. AChE inhibitors have many tial agent for AD treatment [18]. Therefore, further studies side effects, such as nausea, vomiting, diarrhea, abdomi- related to medicinal plants that have antioxidant properties nal pain, dyspepsia, and skin rash [8]. Tacrine has also for the treatment of AD should be conducted. been found to induce hepatotoxicity in clinical trials [10]. Physostigmine was taken out from the drug market due to many disadvantages. Therefore, finding new AChE inhibi- tors, which may be found in medicinal plant resources, Amyloid hypothesis and Alzheimer with less adverse effects is important. drugs targeting β-amyloid The amyloid hypothesis was developed in 1991. It states that the extracellular β-amyloid deposits are the main Antioxidants for the treatment cause of AD [19]. β-amyloid, a short fragment of the of Alzheimer’s disease amyloid precursor protein (APP), is a product of a process- ing error of the APP in the brain. The accumulated clus- Many studies have shown that brain tissues in AD patients ters of β-amyloid proteins are called amyloid plaques. The are subjected to oxidative stress. Oxidative stress leads to amyloid plaques in the brain provoke the destruction of protein oxidation, lipid oxidation, DNA oxidation, and gly- neuronal cells and leads to AD. APP is a long protein con- coxidation [11]. The imbalance in the production of reactive sisting of up to 771 amino acids. APP is cut by two differ- oxygen species (ROS) and antioxidative defense system, ent enzymes leading to the generation of β-amyloid [20]. which is responsible for ROS removal, is characterized by The first β-secretase cuts the APP and then the second oxidative stress. It leads to the age-related neurodegenera- gamma-secretase enzyme cuts one more time to generate tion and cognitive decline [12]. ROS, such as superoxide β-amyloid, which may have a length of 38, 40, or 42 amino − anion radical (O2˙ ), hydrogen peroxide (H2O2), hydroxyl acids. The length of 42 amino acids causes β-amyloid to be 1 radical (˙OH), singlet oxygen ( O2), alkoxyl radicals (RO˙), chemically stickier than the other lengths, thus leading to peroxyl radicals (ROO˙), and reactive nitrogen species clumps and the formation of plaques. (RNS), such as peroxynitrites (ONOO −), enrich many β-Amyloid plaques also provoke the formation of human degenerative diseases [13]. Oxidative stress occurs tangles of tau proteins. These tangles also damage the when ROS and RNS levels exceed the removal capacity of neuronal cells, which lead to dementia [21]. The formation the antioxidant system and cause cell metabolism dysfunc- of β-amyloid plaques also leads to oxidative stress in the tion, leading to several pathological conditions or aging neurons, which in turn, aggravates the development of AD [14]. High levels of protein oxidation, lipid oxidation, DNA [22]. Aβ has several isoforms, but the form of 42 amino acids oxidation, and glycoxidation are the main manifestations has been mainly found in amyloid plaques. Other isoforms during the course of AD [15]. The imbalance of ROS levels have also been found, such as Aβ1−40 and Aβ25−35. Many and antioxidative defense system typically causes oxidative studies have used Aβ1−42 and Aβ25−35 to produce oxidative Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease 415 stress to study the neuroprotection of natural products [32]. Many studies have been conducted to investigate the using different cell lines [23]. When neuronal cell is exposed effects of total medicinal plant extracts on AD as well as to Aβ, this leads to increased ROS production, mitochon- to isolate and identify the active compounds involved [33]. dria dysfunction, and apoptosis
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