Natural Product for the Treatment of Alzheimer's Disease

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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 hyperphosphorylated, 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 inhibitors, 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 as well as the down reg- Many compounds, including lignans, flavonoids, tannins, ulation of antioxidant genes, leading to neuronal cell polyphenols, triterpenes, sterols, and alkaloids, have dysfunction and worsened AD symptoms [24]. APOE4, an shown various beneficial pharmacological activities, such isoform of apolipoprotein, is a major genetic risk factor for as antiinflammatory, anti-amyloidogenic, anticholinester- AD. This APOE4 may induce β-amyloid accumulation in the ase, and antioxidant [32]. Some compounds, such as aged brain [19]. As amyloid plaques are increased in AD patients. garlic extract, curcumin, melatonin, resveratrol, Ginkgo Hence, researchers have proposed that drugs preventing biloba extract, green tea, and vitamins C and E, have been β-amyloid accumulation may be a potential treatment for used in patients with AD and yielded positive results [34– AD. PBT2, a drug candidate, is a second-generation of eight- 36]. Below, we summarize information on some medicinal hydroxyquinoline analog for AD. PBT2 has been shown in plants and isolated compounds that are used for the treat- animal models to effectively detoxify Aβ and increase the ment of AD. clearance of β-amyloid [25]. In a clinical trial, PBT2 at a dose of 250 mg also decreased levels of Aβ1−42 in the brain [26]. Therefore, drugs that can inhibit β-amyloid accumulation may be a strategy for AD treatment. Medicinal plants used for the The β-amyloid plaques in the brain damages neuronal cells by inducing inflammatory reaction. AD is also treatment of Alzheimer’s disease characterized by neuroinflammation features. Cytokines, such as interleukin-1, interleukin-6 (IL-6), and tumor Curcuma longa necrosis factor alpha, have been shown to play a role in the neuroinflammatory process. These cytokines’ expres- Turmeric of Curcuma longa is a rhizomatous perennial sions are increased by β-amyloid peptide. In return, these plant of the ginger family, Zingiberaceae. The active cytokines estimate the accumulation of β-amyloid peptide compounds are water-insoluble curcuminoids, includ- [27]. Some researchers suggested that these cytokines may ing curcumin, demethoxycurcumin, and bis-demethox- play an important role in the progression of AD [28]. The ycurcumin [37]. Curcumin is the main curcuminoid and prolonged use of non-steroidal anti-inflammatory drugs it is responsible for the yellow color of the turmeric root (NSAIDs) has reduced the development of AD and delayed [38]. Curcumin has anti-inflammatory, antioxidant, anti- the onset of the disease [29]. The mechanism of NSAIDs in tumor, antibacterial activities, among others [39, 40]. A decreasing symptoms of Alzheimer may be related to the previous review has shown that curcumin may be a prom- inhibition of the cyclooxygenases (COX) and the activation ising compound for the treatment of AD [41]. According of peroxisome proliferator-activated receptor γ (PPARγ) to another study, when aged mice with β-amyloid plaque [29]. NSAIDs have been shown to suppress the expression accumulation were fed with curcumin, this reduced the of COX, which in turn, stimulates the synthesis of prosta- amount of plaque deposition [42]. Curcumin can decrease glandins and decreases the production of cytokines [30]. oxidative damage status in the brain [43]. In an Alzhei- An in vivo model of transgenic mice with AD and in vitro mer transgenic mouse model, curcumin has been shown model of cell cultures of peripheral, glial, and neuronal to reverse the β-amyloid pathology [44, 45]. Some symp- NSAIDs, such as ibuprofen, indomethacin, and sulindac, toms of AD were also reduced by curcumin’s antioxidant decrease the level of Aβ [29]. However, the beneficial effect and anti-inflammatory properties [45]. In vitro curcumin of NSAIDs in AD treatment are still being discussed due to may inhibit lipid peroxidation and neutralize ROS levels, the limited evidence presented [31]. making it even more potent than vitamin E [46, 47]. Curcumin (with a dose of 5–10 μM) protected PC12 cells against Aβ-induced neurotoxicity by inhibiting oxidative damage and tau hyperphosphorylation [42]. In a clini- Herbal medicine for the treatment cal trial, curcumin has shown several beneficial effects of Alzheimer’s disease on healthy middle aged people, including lowering the plasma β-amyloid protein concentrations [48]. More Medicinal plants have been shown to decrease the pro- experiments are needed to evaluate the exact mechanism gress and symptoms of various diseases, including AD of C. longa. 416 Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease

Bacopa monnieri memory in rats were significantly enhanced by feeding them with the ethanolic extract of C. pluricaulis and its Bacopa monnieri is commonly used in traditional medicine ethyl acetate and water fractions [60]. The oral admin- as a nerve tonic, diuretic, and a cardiotonic agent as well as istration of C. pluricaulis also alleviated the neurotoxic for the treatment of asthma and rheumatism. It also applied effect of scopolamine by reducing the induction of for epilepsy, insomnia [49]. The main compounds of B. mon- protein and mRNA levels of tau and AβPP [61]. Unfortu- nieri are saponins and triterpenoids. These compounds, nately, no clinical data exist on the effects of C. pluricaulis such as bacopasides III, bacopasides IV, bacopasides V, on AD patients. Further investigations are thus needed to bacosides A, bacosides B, bacosaponins A, bacosaponins B, explore the potential favorable effects of C. pluricaulis on and bacosaponins C, have been isolated from B. monnieri. AD treatment. The presence of some saponin glycosides, such as jujubo- genin bisdesmosides bacopasaponins D, bacopasaponins E, and bacopasaponins F, in B. monnieri has also been reported. Centella asiatica Furthermore, other compounds, including alkaloids, sterols, betulic acid, polyphenols, and sulfhydryl, which have anti- Traditional medicines have used Centella asiatica for rejuve- oxidant activities, have also been found in B. monnieri [50]. nating the neuronal cells. It has also been used for increas- Traditional medicine has used B. monnieri for improving ing intelligence, longevity, and memory [52]. Asiatic acid memory and cognitive function [51]. Many studies related and asiaticoside have been isolated from C. asiatica, and to neuropharmacological effects and nootropic action of these compounds have shown the ability to reduce H2O2- B. monnieri extracts have been conducted extensively [52]. induced cell cytotoxicity, decrease free radical levels, and In the hippocampus, B. monnieri augments protein kinase inhibit β-amyloid cell damages in vitro. C. asiatica extracts activity, which provides a nootropic action [53]. In an reduced the β-amyloid pathology and decreased the oxida- animal Alzheimer model, rats fed with B. monnieri extract tive stress response in the brains of a mice model of AD showed decreased cholinergic degeneration and exhibited [62]. It has already been reported that C. asiatica ethanol cognition-enhancing effect [54]. Another study reported extracts can protect neuronal cells against Aβ1−40-induced that B. monnieri inhibited the AChE activity and increased neurotoxicity. C. asiatica can also decrease ROS produc- ACh levels [55]. Moreover, B. monnieri extracts also protected tion and modulate the antioxidative defense system in neuronal cells from damages caused by β-amyloids. More- cells by enhancing the activities of superoxide dismutase, over, neuronal cells treated with B. monnieri extract exhib- catalase, glutathione peroxidase, glutathione reductase, ited lower levels of ROS, suggesting that B. monnieri reduced and levels of glutathione and glutathione disulfide [63]. intracellular oxidative stress [56]. A clinical trial of AD These activities suggest the important role of C. asiatica for patients showed that the polyherbal formulation containing the prevention and treatment of AD [64]. B. monnieri extract effectively improved the cognitive functions and decreased the level of inflammation and oxidative stress in patients [57]. Nevertheless, detailed investigations Ginkgo biloba are needed to further assess the potential neuroprotective action of B. monnieri against AD. Ginkgo biloba leaves have been used in traditional medicine as an agent for improving memory and age-related deterioration. The phytochemicals of Ginkgo biloba Convolvulus pluricaulis leaf extracts contain flavonoids, organic acids, and ter- enoids, which provide neuroprotective activity. The pro- The phytochemicals of Convolvulus pluricaulis reveal tective mechanism of Ginkgo biloba leaf extracts against that it may contain active compounds, such as triterpe- β-amyloid has been shown to induce cytotoxicity and noids, flavonol glycosides, anthocyanins, and steroids. may be related to the capacity to scavenge free radicals, They provide the nootropic and memory-enhancing reduce mitochondrial dysfunction, activate JNK and ERK activity for C. pluricaulis [58]. Another study reported pathways, and prevent neuronal apoptosis. Bilobalide that C. pluricaulis may calm the nerves by regulating is a principal terpenoid compound isolated from Ginkgo stress hormone, adrenaline, and cortisol levels in the biloba leaves; it has potent protective effects on neurons body [58]. Traditional medicines have used C. pluricau- and Schwann cells [65]. Bilobalide has been shown to lis for nervous system-related diseases, including stress, reduce the expression of p53, Bax, and caspase-3 proteins anxiety, mental fatigue, and insomnia [59]. Learning and as well as inhibite ROS-induced apoptosis in PC12 cells Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease 417

[66]. Bilobalide also stimulated neurogenesis and synap- Others togenesis by increasing the levels of transcription factor phosphorylated CREB and neurotrophin BDNF in neu- Some natural product compounds have also been isolated ronal cells [67]. Furthermore, the clinical trial of market- from medicinal plants for the treatment of AD. ing a dietary supplement containing Ginkgo biloba extract was beneficial in treating cognitive decline in the aging Quercetin process and in the early stages of AD [68].

Zingiber officinaleis

Zingiber officinaleis has been widely used in food supplements as extracts or as ingredients of ginger tea. Principal compounds, such as gingerols, shagols, bisabolene, zingiberene, and monoterpenes, have been isolated from Z. officinaleis [69]. In vitro assays have shown the AChE Quercetin is a flavonoid compound found in a wide variety inhibitory activity of Z. officinaleis. Inhibiting the AChE of medicinal plants, such as apples, onions, berries, green enzyme increases ACh levels in synapses, augments the tea, and red wine. Quercetin has a strong antioxidant activity of cholinergic pathways, and enhances cognitive activity by scavenging ROS [76]. In addition, it has other functions in AD patients. Furthermore, Z. officinaleis has beneficial properties, including anticancer, antiviral, anti- the ability to inhibit lipid peroxidation and provide the inflammatory, and antiamyloidogenic properties [77, 78]. protective effect against AD. An in vivo assay has reported Quercetin at a dose of 10 μM has shown antiamyloidogenic reduced levels of lipid peroxidation in rats fed with activity by inhibiting the accumulation of β-amyloids [79]. Z. officinaleis extract. The mechanism may be explained Quercetin also reduced the Aβ-induced apoptosis in neu- by the ability of Z. officinaleis extract to reduce the over- ronal cells. However, at a higher dose (40 μM), quercetin stimulation of N-methyl-D-aspartate (NMDA) receptors may induce cytotoxicity [80]. A recent study has shown and prevent the formation of free radicals [70]. that nanoencapsulated quercetin in zein nanoparticles significantly improved cognition and memory impair- ments on senescence-accelerated P8 mice. The mecha- Allium sativum nism may be related to the decreased expression of the hippocampal astrocyte marker GFAP [81]. Allium sativum has been used in food and medicinal supplements. Borek et al. have investigated the neuroprotective effect of the aged garlic extract in a Tg2576 mice Epigallocatechin-3-gallate model, in which mice fed with aged garlic extracts exhibited enhanced memory in the hippocampal region [71]. The mechanism has scavenged the free radicals; increased enzyme antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels; inhibited lipid peroxidation level; and reduced inflammatory prostaglandins [72]. Moreover, aged garlic extracts inhibited 3-hydroxy-3-methylglutaryl-CoA reductase and reduced cholesterol synthesis. Aged garlic extracts can also protect neurons from β-amyloid neurotoxicity and apoptosis, preventing cognitive decline, ischemia or reperfusion-related neuronal death, and enhancing learning and memory retention [73]. A recent study has reported that aged garlic Epigallocatechin-3-gallate is a flavonoid-type catechin extracts were useful in enhancing the short-term recog- found in Camellia sinensis. Epigallocatechin-3-gallate nition memory and reducing the neuroinflammation in has potent antioxidant activity, and many studies have Aβ-induced rats [74] as well as in attenuating neuroinflam- investigated the effects of epigallocatechin-3-gallate on matory responses in microglial cells [75]. various diseases, including cancer and cardiovascular and 418 Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease neurodegenerative diseases [82]. Epigallocatechin-3-gallate Resveratrol has been shown to increase glutathione peroxidase activity, inhibit the AChE activity and inhibit NO metabolite formation and ROS generation in streptozotocin-induced dementia in mice [83]. Epigallocatechin-3-gallate also increased memory formation and inhibited γ-secretase enzyme activity in mutant PS2 Alzheimer mice [84]. Furthermore, epigallocatechin-3-gallate prevented LPS-induced memory loss and apoptosis by decreasing amyloid precursor protein expression, inhibiting beta-site APP cleaving enzyme 1 Resveratrol is a polyphenolic compound belonging to activity, and reducing β-amyloid accumulation. Moreover, the group stilbenes. Resveratrol can be found in red it has also been shown to reduce the expression of inflam- wine, nuts, and the skin of grapes and other fruits [94]. matory factors, such as tumor necrosis factor-α (TNF-α), Many studies have shown that it has anti-cancer, anti- interleukin 1β, IL-6, inducible nitric oxide synthase (iNOS), inflammatory, antioxidant, and protective cardiovascular cyclooxygenase-2 (COX-2), soluble intracellular adhesion, properties, can lower blood glucose levels, and neuropro- and molecule-1 macrophage colony-stimulating factor, and tective effects [95]. Resveratrol has a potent antioxidant to prevent astrocyte activation in neuronal cells [85, 86]. activity by scavenging ROS, increasing gluthatione levels, Epigallocatechin-3-gallate has also been shown to reduce and improving the endogenous antioxidants [96]. Resver- Aβ accumulation and elevate neprilysin enzyme expres- atrol can also reduce the level of β-amyloids by inducing sion, which is the rate-limiting degradation enzyme of Aβ in the non-amyloidogenic cleavage of APP and enhancing senescence-accelerated P8 mice [87]. the clearance of β-amyloid [95]. Resveratrol (15, 45, and 135 mg/kg) also inhibited AChE activity in neuronal cells [97]. A randomized, double-blind, placebo-controlled Berberine trial of resveratrol for AD provided evidence that resveratrol is safe, well-tolerated, and has the ability to reduce CSF Aβ40 and plasma Aβ40 levels [98]. Recently, He et al. [99] provided evidence proving that resveratrol protects against hyperphosphorylation and/or mediates dephos- phorylation of the tau protein. Moroever, they found that resveratrol ameliorated the deleterious effects in a rat model for AD by alleviating cholinergic pathways, thus reducing oxidative stress and improving spatial memory [100]. Evidence that resveratrol may modulate neuroinflammation and induces adaptive immunity by the activation of SIRT1 has also been presented [101]. Berberine is a quaternary ammonium salt and a type of isoquinoline alkaloids, isolated from Coptis chinensis [88]. Huperzine A Berberine has many biological activities, such as antioxidant activity, inhibition of AChE and butyrylcholinesterase, monoamine oxidase, and cholesterol-lowering activity [88]. Tg mice fed with berberine at a dose of 100 mg/kg via oral administration showed significantly increasing learning and spatial memory [89]. BV2 microglia cells treated with berberine significantly reduced the β-amyloid-induced expressions of IL-6, COX-2, and iNOS [90]. In addition, berberine also strongly reduced the expression of NF-κB by inhibiting the PI3K/protein kinase B and MAPK pathways Huperzine A is a sesquiterpene alkaloid group found in [91]. A recent study has shown that berberine can signifi- Huperzia serrate. Traditional medicine has used Huper- cantly ameliorate memory impairment, reduce Aβ and APP zine A for the treatment of fever and swelling. H. serrate levels, reduce Aβ plaque deposition in the hippocampus extract can also be used as a food supplement for improv- [92], and prevent the increase of AChE activity [93]. ing memory [102]. Huperzine A has a strong effect on the Bui and Nguyen: Natural product for the treatment of Alzheimer’s disease 419 inhibition of AChE. Its mechanism is similar to those of [112]. Rosmarinic acid may also prevent locomotor activity, rivastigmine, donepezil, and galantamine, which have short-term spatial memory, and biochemical alterations of been used for AD treatment. The new tacrine-Huperzine brain tissue found in a rat model of AD by reducing lipid A combination (called Huprines) is a potent AChE inhibi- peroxidation and inflammatory process [113]. Clinical trial tors that can significantly reduce Aβ-induced memory studies are needed to further demonstrate the efficiency of injury [103]. Clinical trials have shown that huperzine A rosmarinic acid against AD. has very low minimal adverse reactions, such as gastro- enteric symptoms, dizziness, headaches, nausea, and Luteolin reduced heart rate. This is an advantage of huperzine A compared with other drug AChE inhibitors for AD treatment [102]. Huperzine A can potentially inhibit several apoptotic factors, including caspase-3, Bax, and p53. Huperzine A also regulated the expression and secretion of the nerve growth factor [104]. Huperzine A enhanced learning capacity and memory in Tg mice in a Morris water maze test. The mechanism can be explained by the inhibition of PKC/MAPK, γ-secretases, and BACE as well as in the increase of phospho GSK-3 [105]. Huperzine A also Luteolin is a flavonoid compound found in many medici- reduced the β-amyloid plaques and oligomeric A amount nal plants, such as Magnoliophyta, Pteridophyta, Bryo- in the cortex and hippocampus [106]. Moreover, huperzine phyta, and Pinophyta [114]. Luteolin has been shown to A can inhibit the NMDA receptor and potassium chanel have many biological activities, such as anti-inflamma- in the brain [107]. A phase II trial of huperzine A in mild tory, antioxidant, anticancer, antimicrobial, and neu- to moderate AD showed that huperzine A 200 μg did not roprotective effects [115]. Luteolin can also reduce the demonstrate cognitive benefits; however, the huperzine A zinc-induced hyperphosphorylation of the tau protein, 400 μg can improve the Alzheimer’s Disease Assessment the mechanism of which may be explained by its antioxi- Scale-cognitive [108]. Still, further studies are needed to dant activity and ability to regulate the tau phosphatase/ fully elucidate the efficiency of huperzine A against AD. kinase system [116]. Furthermore, luteolin can decrease the expression of amyloid precursor protein and reduced Rosmarinic acid the formation of β-amyloids [117]. Luteolin can also also inhibit apoptosis by decreasing intracellular ROS generation; improving antioxidant endogenous system; such as augmenting SOD, CAT and GPx activities; and activating the NRF2 pathway [118]. Luteolin has also been shown to have the ability to relieve the cognitive dysfunction, improve significantly antioxidant system, decrease the lipid peroxide production, and inhibit inflammatory reaction in the brain tissue of rats induced by chronic Rosmarinic acid is a polyphenol-type carboxylic acid cerebral hypoperfusion [119]. In another study, luteolin existed in many Lamiaceae speies [109]. Rosmarinic acid also improved the cognition function and memory on a has many pharmacological activities, such as antioxidant, streptozotocin-induced AD rat model [120]. Despite these antibacterial, anti-inflammatory, anticancer, antiviral, studies, further clinical trial data are needed to confirm and neuroprotective effects [110]. Rosmarinic acid may the protective effects of luteolin against AD. significantly prevent β-amyloid-induced memory loss, the mechanism of which may be attributed to its capacity to inhibit NF-κB and TNF-α expressions [111]. Rosmarinic acid has also been shown to protect neuronal PC12 cells Conclusions to avoid beta-amyloid-induced cytotoxicity. Further- more, it may decrease the hyperphosphorylation of the Many valuable medicinal plants can be applied to reduce tau protein. Inhibiting apoptotic pathways by rosmarinic dementia and treat AD. 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