Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu / Tam, Joseph


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

Online
ISSN
2191-0286
See all formats and pricing
More options …
Volume 28, Issue 5

Issues

Natural product for the treatment of Alzheimer’s disease

Thanh Tung Bui
  • Corresponding author
  • School of Medicine and Pharmacy, Vietnam National University, Hanoi, Office 506, Building Y1, 144 XuanThuy, Cau Giay, Ha Noi, Vietnam, Tel.: +84-4-85876172, Fax: +84-0437450188
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thanh Hai Nguyen
Published Online: 2017-07-14 | DOI: https://doi.org/10.1515/jbcpp-2016-0147

Abstract

Alzheimer’s disease (AD) is related to increasing age. It is mainly characterized by progressive neurodegenerative disease, which damages memory and cognitive function. Natural products offer many options to reduce the progress and symptoms of many kinds of diseases, including AD. Meanwhile, natural compound structures, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, have anti-inflammatory, antioxidant, anti-amyloidogenic, and anticholinesterase activities. In this review, we summarize the pathogenesis and targets for treatment of AD. We also present several medicinal plants and isolated compounds that are used for preventing and reducing symptoms of AD.

Keywords: acetylcholinesterase enzyme; Alzheimer’s disease; β-amyloid; natural product

Introduction

Alzheimer’s disease (AD) is a disease related to aging. It is neurodegenerative disease that leads to memory loss and impaired cognitive function. The reports of the World Health Organization in 2012 showed that over 35.6 million people in the world have dementia, and about 60%–70% 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].

Pathogenesis of Alzheimer’s disease

Until now, the pathogenesis of AD is not yet completely understood. The genetic susceptibility and environmental factors are responsible for late onset sporadic AD, which is the most common form of the disease. Many studies have attempted to understand the disease mechanism and develop a disease-modifying drug. Two main factors are responsible for the development of AD: β-amyloid protein and abnormal tau protein, or both of them. AD is characteristized by the overproduction of β-amyloid proteins (Aβ) and hyperphosphorylated Tau protein, which can lead to the loss of synaptic connections and neurons in the hippocampus and cerebral cortex, a decline in cognitive function, and dementia [2]. The accumulation of β-amyloid protein and neurofibrillary tangles have been shown in AD patients. The overproduction and accumulation of Aβ lead to oxidation, lipid peroxidation, inflammation, disturbance of cell functions, and apoptosis and formation of neurofibrillary tangles [3]. The tau protein is hyperphosphorylated, which leads to the formation of tangles deposited in the hippocampus and, ultimately, to cell death [4]. Many biochemical changes within cells, such as oxidative stress, inflammation, metabolic disturbances, disruption of Ca2+ homeostasis, and the accumulation of unfolded/mis-folded proteins, have been demonstrated to induce neuronal cell death in AD patients [5]. The two mechanisms involved in AD are oxidative damage and inflammatory process, and both of these have been studied well in the literature.

Acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease

Cholinergic hypothesis is an important hypothesis that is used to explain the pathogenesis of AD. This hypothesis explains that AD is caused by a decrease in neurotransmitter acetylcholine (Ach). Many drugs used in the treatment of AD are based on cholinergic hypothesis [6]. ACh, serotonin, and norepinephrine are neurotransmitter deficits in the brain that occur because of cell death. Many studies have shown that a low level of neurotransmitters in a cholinergic system is responsible for cognitive decline and memory loss in AD patients [6], [7], [8], [9]. Acetylcholinesterase (AChE) is a main enzyme that degrades the ACh neurotransmitter. Various therapeutic strategies elevate ACh neurotransmitter levels, then increase cholinergic transmission by inhibiting ACh hydrolysis with AChE inhibitors, stimulating nicotinic and muscarinic receptors or using cholinomimetic substances [9]. Drugs such as galantamine, tacrine, donepezil, metrifonate or rivastigmine inhibit AChE, augment the level of Ach, and improves cholinergic transmission. These drugs have been used to alleviate the symptoms of AD, which are caused by the degeneration of cholinergic neurons and injured transmission. However, the inhibition of AChE has not been very effective in the treatment of Alzheimer [9]. AChE inhibitors have many side effects, such as nausea, vomiting, diarrhea, abdominal pain, dyspepsia, and skin rash [8]. Tacrine has also 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, with less adverse effects is important.

Antioxidants for the treatment of Alzheimer’s disease

Many studies have shown that brain tissues in AD patients are subjected to oxidative stress. Oxidative stress leads to protein oxidation, lipid oxidation, DNA oxidation, and glycoxidation [11]. The imbalance in the production of reactive oxygen species (ROS) and antioxidative defense system, which is responsible for ROS removal, is characterized by oxidative stress. It leads to the age-related neurodegeneration and cognitive decline [12]. ROS, such as superoxide anion radical (O2˙), hydrogen peroxide (H2O2), hydroxyl radical (˙OH), singlet oxygen (1O2), alkoxyl radicals (RO˙), peroxyl radicals (ROO˙), and reactive nitrogen species (RNS), such as peroxynitrites (ONOO−), enrich many human degenerative diseases [13]. Oxidative stress occurs when ROS and RNS levels exceed the removal capacity of the antioxidant system and cause cell metabolism dysfunction, leading to several pathological conditions or aging [14]. High levels of protein oxidation, lipid oxidation, DNA oxidation, and glycoxidation are the main manifestations during the course of AD [15]. The imbalance of ROS levels and antioxidative defense system typically causes oxidative stress in AD patients. Hence, antioxidant treatment is a promising strategy for inhibiting disease progression.

A recent study has shown the link between antioxidant intake and reduced symptoms of dementia [16]. Treatment with antioxidants, such as those found n vitamin E, vitamin C, selegiline, estrogen, and Ginkgo biloba, may inhibit the development of AD [17]. Furthermore, some medicinal plants with antioxidant activities also exhibit potential for AD treatment. Jung et al. have reported that three major alkaloids in Coptidis rhizoma, including groenlandicine, berberine, and palmatine, can potentially exhibit anti-AD effects by inhibiting AChE activity and Aβ accumulation, and also present antioxidant capacities to inhibit ROS and RNS levels [13]. Silibinin, an isolated flavonoid from Silybum marianum, also has an antioxidant property. Silibinin has been shown to prevent memory impairment and oxidative damage induced by Aβ in mice model, making it a potential agent for AD treatment [18]. Therefore, further studies related to medicinal plants that have antioxidant properties for the treatment of AD should be conducted.

Amyloid hypothesis and Alzheimer drugs targeting β-amyloid

The amyloid hypothesis was developed in 1991. It states that the extracellular β-amyloid deposits are the main cause of AD [19]. β-amyloid, a short fragment of the amyloid precursor protein (APP), is a product of a processing error of the APP in the brain. The accumulated clusters of β-amyloid proteins are called amyloid plaques. The amyloid plaques in the brain provoke the destruction of neuronal cells and leads to AD. APP is a long protein consisting of up to 771 amino acids. APP is cut by two different enzymes leading to the generation of β-amyloid [20]. The first β-secretase cuts the APP and then the second gamma-secretase enzyme cuts one more time to generate β-amyloid, which may have a length of 38, 40, or 42 amino acids. The length of 42 amino acids causes β-amyloid to be chemically stickier than the other lengths, thus leading to clumps and the formation of plaques.

β-Amyloid plaques also provoke the formation of tangles of tau proteins. These tangles also damage the neuronal cells, which lead to dementia [21]. The formation of β-amyloid plaques also leads to oxidative stress in the neurons, which in turn, aggravates the development of AD [22]. Aβ has several isoforms, but the form of 42 amino acids has been mainly found in amyloid plaques. Other isoforms have also been found, such as Aβ1−40 and Aβ25−35. Many studies have used Aβ1−42 and Aβ25−35 to produce oxidative stress to study the neuroprotection of natural products using different cell lines [23]. When neuronal cell is exposed to Aβ, this leads to increased ROS production, mitochondria dysfunction, and apoptosis as well as the down regulation of antioxidant genes, leading to neuronal cell dysfunction and worsened AD symptoms [24]. APOE4, an isoform of apolipoprotein, is a major genetic risk factor for AD. This APOE4 may induce β-amyloid accumulation in the brain [19]. As amyloid plaques are increased in AD patients. Hence, researchers have proposed that drugs preventing β-amyloid accumulation may be a potential treatment for AD. PBT2, a drug candidate, is a second-generation of eight-hydroxyquinoline analog for AD. PBT2 has been shown in animal models to effectively detoxify Aβ and increase the 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.

The β-amyloid plaques in the brain damages neuronal cells by inducing inflammatory reaction. AD is also characterized by neuroinflammation features. Cytokines, such as interleukin-1, interleukin-6 (IL-6), and tumor necrosis factor alpha, have been shown to play a role in the neuroinflammatory process. These cytokines’ expressions are increased by β-amyloid peptide. In return, these cytokines estimate the accumulation of β-amyloid peptide [27]. Some researchers suggested that these cytokines may play an important role in the progression of AD [28]. The prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) has reduced the development of AD and delayed the onset of the disease [29]. The mechanism of NSAIDs in decreasing symptoms of Alzheimer may be related to the inhibition of the cyclooxygenases (COX) and the activation of peroxisome proliferator-activated receptor γ (PPARγ) [29]. NSAIDs have been shown to suppress the expression of COX, which in turn, stimulates the synthesis of prostaglandins and decreases the production of cytokines [30]. An in vivo model of transgenic mice with AD and in vitro model of cell cultures of peripheral, glial, and neuronal NSAIDs, such as ibuprofen, indomethacin, and sulindac, decrease the level of Aβ [29]. However, the beneficial effect of NSAIDs in AD treatment are still being discussed due to the limited evidence presented [31].

Herbal medicine for the treatment of Alzheimer’s disease

Medicinal plants have been shown to decrease the progress and symptoms of various diseases, including AD [32]. Many studies have been conducted to investigate the effects of total medicinal plant extracts on AD as well as to isolate and identify the active compounds involved [33]. Many compounds, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, have shown various beneficial pharmacological activities, such as antiinflammatory, anti-amyloidogenic, anticholinesterase, and antioxidant [32]. Some compounds, such as aged garlic extract, curcumin, melatonin, resveratrol, Ginkgo biloba extract, green tea, and vitamins C and E, have been used in patients with AD and yielded positive results [34], [35], [36]. Below, we summarize information on some medicinal plants and isolated compounds that are used for the treatment of AD.

Medicinal plants used for the treatment of Alzheimer’s disease

Curcuma longa

Turmeric of Curcuma longa is a rhizomatous perennial plant of the ginger family, Zingiberaceae. The active compounds are water-insoluble curcuminoids, including curcumin, demethoxycurcumin, and bis-demethoxycurcumin [37]. Curcumin is the main curcuminoid and it is responsible for the yellow color of the turmeric root [38]. Curcumin has anti-inflammatory, antioxidant, antitumor, antibacterial activities, among others [39], [40]. A previous review has shown that curcumin may be a promising compound for the treatment of AD [41]. According to another study, when aged mice with β-amyloid plaque accumulation were fed with curcumin, this reduced the amount of plaque deposition [42]. Curcumin can decrease oxidative damage status in the brain [43]. In an Alzheimer transgenic mouse model, curcumin has been shown to reverse the β-amyloid pathology [44], [45]. Some symptoms of AD were also reduced by curcumin’s antioxidant and anti-inflammatory properties [45]. In vitro curcumin may inhibit lipid peroxidation and neutralize ROS levels, 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 clinical trial, curcumin has shown several beneficial effects on healthy middle aged people, including lowering the plasma β-amyloid protein concentrations [48]. More experiments are needed to evaluate the exact mechanism of C. longa.

Bacopa monnieri

Bacopa monnieri is commonly used in traditional medicine as a nerve tonic, diuretic, and a cardiotonic agent as well as for the treatment of asthma and rheumatism. It also applied for epilepsy, insomnia [49]. The main compounds of B. monnieri are saponins and triterpenoids. These compounds, such as bacopasides III, bacopasides IV, bacopasides V, bacosides A, bacosides B, bacosaponins A, bacosaponins B, and bacosaponins C, have been isolated from B. monnieri. The presence of some saponin glycosides, such as jujubogenin bisdesmosides bacopasaponins D, bacopasaponins E, and bacopasaponins F, in B. monnieri has also been reported. Furthermore, other compounds, including alkaloids, sterols, betulic acid, polyphenols, and sulfhydryl, which have antioxidant activities, have also been found in B. monnieri [50]. Traditional medicine has used B. monnieri for improving memory and cognitive function [51]. Many studies related to neuropharmacological effects and nootropic action of B. monnieri extracts have been conducted extensively [52]. In the hippocampus, B. monnieri augments protein kinase activity, which provides a nootropic action [53]. In an animal Alzheimer model, rats fed with B. monnieri extract showed decreased cholinergic degeneration and exhibited cognition-enhancing effect [54]. Another study reported that B. monnieri inhibited the AChE activity and increased ACh levels [55]. Moreover, B. monnieri extracts also protected neuronal cells from damages caused by β-amyloids. Moreover, neuronal cells treated with B. monnieri extract exhibited lower levels of ROS, suggesting that B. monnieri reduced intracellular oxidative stress [56]. A clinical trial of AD patients showed that the polyherbal formulation containing B. monnieri extract effectively improved the cognitive functions and decreased the level of inflammation and oxidative stress in patients [57]. Nevertheless, detailed investigations are needed to further assess the potential neuroprotective action of B. monnieri against AD.

Convolvulus pluricaulis

The phytochemicals of Convolvulus pluricaulis reveal that it may contain active compounds, such as triterpenoids, flavonol glycosides, anthocyanins, and steroids. They provide the nootropic and memory-enhancing activity for C. pluricaulis [58]. Another study reported that C. pluricaulis may calm the nerves by regulating stress hormone, adrenaline, and cortisol levels in the body [58]. Traditional medicines have used C. pluricaulis for nervous system-related diseases, including stress, anxiety, mental fatigue, and insomnia [59]. Learning and memory in rats were significantly enhanced by feeding them with the ethanolic extract of C. pluricaulis and its ethyl acetate and water fractions [60]. The oral administration of C. pluricaulis also alleviated the neurotoxic effect of scopolamine by reducing the induction of protein and mRNA levels of tau and AβPP [61]. Unfortunately, no clinical data exist on the effects of C. pluricaulis on AD patients. Further investigations are thus needed to explore the potential favorable effects of C. pluricaulis on AD treatment.

Centella asiatica

Traditional medicines have used Centella asiatica for rejuvenating the neuronal cells. It has also been used for increasing intelligence, longevity, and memory [52]. Asiatic acid and asiaticoside have been isolated from C. asiatica, and these compounds have shown the ability to reduce H2O2-induced cell cytotoxicity, decrease free radical levels, and inhibit β-amyloid cell damages in vitro. C. asiatica extracts reduced the β-amyloid pathology and decreased the oxidative stress response in the brains of a mice model of AD [62]. It has already been reported that C. asiatica ethanol extracts can protect neuronal cells against Aβ1−40-induced neurotoxicity. C. asiatica can also decrease ROS production and modulate the antioxidative defense system in cells by enhancing the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and levels of glutathione and glutathione disulfide [63]. These activities suggest the important role of C. asiatica for the prevention and treatment of AD [64].

Ginkgo biloba

Ginkgo biloba leaves have been used in traditional medicine as an agent for improving memory and age-related deterioration. The phytochemicals of Ginkgo biloba leaf extracts contain flavonoids, organic acids, and terenoids, which provide neuroprotective activity. The protective mechanism of Ginkgo biloba leaf extracts against β-amyloid has been shown to induce cytotoxicity and may be related to the capacity to scavenge free radicals, reduce mitochondrial dysfunction, activate JNK and ERK pathways, and prevent neuronal apoptosis. Bilobalide is a principal terpenoid compound isolated from Ginkgo biloba leaves; it has potent protective effects on neurons and Schwann cells [65]. Bilobalide has been shown to reduce the expression of p53, Bax, and caspase-3 proteins as well as inhibite ROS-induced apoptosis in PC12 cells [66]. Bilobalide also stimulated neurogenesis and synaptogenesis by increasing the levels of transcription factor phosphorylated CREB and neurotrophin BDNF in neuronal cells [67]. Furthermore, the clinical trial of marketing a dietary supplement containing Ginkgo biloba extract was beneficial in treating cognitive decline in the aging 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 inhibitory activity of Z. officinaleis. Inhibiting the AChE enzyme increases ACh levels in synapses, augments the activity of cholinergic pathways, and enhances cognitive functions in AD patients. Furthermore, Z. officinaleis has the ability to inhibit lipid peroxidation and provide the protective effect against AD. An in vivo assay has reported reduced levels of lipid peroxidation in rats fed with Z. officinaleis extract. The mechanism may be explained by the ability of Z. officinaleis extract to reduce the overstimulation of N-methyl-D-aspartate (NMDA) receptors and prevent the formation of free radicals [70].

Allium sativum

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 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 extracts were useful in enhancing the short-term recognition memory and reducing the neuroinflammation in Aβ-induced rats [74] as well as in attenuating neuroinflammatory responses in microglial cells [75].

Others

Some natural product compounds have also been isolated from medicinal plants for the treatment of AD.

Quercetin

Quercetin is a flavonoid compound found in a wide variety of medicinal plants, such as apples, onions, berries, green tea, and red wine. Quercetin has a strong antioxidant activity by scavenging ROS [76]. In addition, it has other beneficial properties, including anticancer, antiviral, antiinflammatory, and antiamyloidogenic properties [77], [78]. Quercetin at a dose of 10 μM has shown antiamyloidogenic activity by inhibiting the accumulation of β-amyloids [79]. Quercetin also reduced the Aβ-induced apoptosis in neuronal cells. However, at a higher dose (40 μM), quercetin may induce cytotoxicity [80]. A recent study has shown that nanoencapsulated quercetin in zein nanoparticles significantly improved cognition and memory impairments on senescence-accelerated P8 mice. The mechanism may be related to the decreased expression of the hippocampal astrocyte marker GFAP [81].

Epigallocatechin-3-gallate

Epigallocatechin-3-gallate is a flavonoid-type catechin found in Camellia sinensis. Epigallocatechin-3-gallate has potent antioxidant activity, and many studies have investigated the effects of epigallocatechin-3-gallate on various diseases, including cancer and cardiovascular and neurodegenerative diseases [82]. Epigallocatechin-3-gallate 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 activity, and reducing β-amyloid accumulation. Moreover, it has also been shown to reduce the expression of inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin 1β, IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), soluble intracellular adhesion, and molecule-1 macrophage colony-stimulating factor, and to prevent astrocyte activation in neuronal cells [85], [86]. Epigallocatechin-3-gallate has also been shown to reduce Aβ accumulation and elevate neprilysin enzyme expression, which is the rate-limiting degradation enzyme of Aβ in senescence-accelerated P8 mice [87].

Berberine

Berberine is a quaternary ammonium salt and a type of isoquinoline alkaloids, isolated from Coptis chinensis [88]. 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 [91]. A recent study has shown that berberine can significantly ameliorate memory impairment, reduce Aβ and APP levels, reduce Aβ plaque deposition in the hippocampus [92], and prevent the increase of AChE activity [93].

Resveratrol

Resveratrol is a polyphenolic compound belonging to the group stilbenes. Resveratrol can be found in red wine, nuts, and the skin of grapes and other fruits [94]. Many studies have shown that it has anti-cancer, anti-inflammatory, antioxidant, and protective cardiovascular properties, can lower blood glucose levels, and neuroprotective effects [95]. Resveratrol has a potent antioxidant activity by scavenging ROS, increasing gluthatione levels, and improving the endogenous antioxidants [96]. Resveratrol can also reduce the level of β-amyloids by inducing the non-amyloidogenic cleavage of APP and enhancing 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 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 dephosphorylation 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 neuro-inflammation and induces adaptive immunity by the activation of SIRT1 has also been presented [101].

Huperzine A

Huperzine A is a sesquiterpene alkaloid group found in Huperzia serrate. Traditional medicine has used Huperzine A for the treatment of fever and swelling. H. serrate extract can also be used as a food supplement for improving memory [102]. Huperzine A has a strong effect on the inhibition of AChE. Its mechanism is similar to those of rivastigmine, donepezil, and galantamine, which have been used for AD treatment. The new tacrine-Huperzine A combination (called Huprines) is a potent AChE inhibitors that can significantly reduce Aβ-induced memory injury [103]. Clinical trials have shown that huperzine A has very low minimal adverse reactions, such as gastroenteric symptoms, dizziness, headaches, nausea, and 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 reduced the β-amyloid plaques and oligomeric A amount in the cortex and hippocampus [106]. Moreover, huperzine A can inhibit the NMDA receptor and potassium chanel in the brain [107]. A phase II trial of huperzine A in mild to moderate AD showed that huperzine A 200 μg did not demonstrate cognitive benefits; however, the huperzine A 400 μg can improve the Alzheimer’s Disease Assessment Scale-cognitive [108]. Still, further studies are needed to fully elucidate the efficiency of huperzine A against AD.

Rosmarinic acid

Rosmarinic acid is a polyphenol-type carboxylic acid existed in many Lamiaceae speies [109]. Rosmarinic acid has many pharmacological activities, such as antioxidant, antibacterial, anti-inflammatory, anticancer, antiviral, and neuroprotective effects [110]. Rosmarinic acid may 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 to avoid beta-amyloid-induced cytotoxicity. Furthermore, it may decrease the hyperphosphorylation of the tau protein. Inhibiting apoptotic pathways by rosmarinic acid may be explained due to its capacity to inhibit ROS formation, caspase-3 activation, and DNA fragmentation [112]. Rosmarinic acid may also prevent locomotor activity, short-term spatial memory, and biochemical alterations of brain tissue found in a rat model of AD by reducing lipid peroxidation and inflammatory process [113]. Clinical trial studies are needed to further demonstrate the efficiency of rosmarinic acid against AD.

Luteolin

Luteolin is a flavonoid compound found in many medicinal plants, such as Magnoliophyta, Pteridophyta, Bryophyta, and Pinophyta [114]. Luteolin has been shown to have many biological activities, such as anti-inflammatory, antioxidant, anticancer, antimicrobial, and neuroprotective effects [115]. Luteolin can also reduce the zinc-induced hyperphosphorylation of the tau protein, the mechanism of which may be explained by its antioxidant activity and ability to regulate the tau phosphatase/kinase system [116]. Furthermore, luteolin can decrease the expression of amyloid precursor protein and reduced 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 cerebral hypoperfusion [119]. In another study, luteolin also improved the cognition function and memory on a streptozotocin-induced AD rat model [120]. Despite these studies, further clinical trial data are needed to confirm the protective effects of luteolin against AD.

Conclusions

Many valuable medicinal plants can be applied to reduce dementia and treat AD. The main chemical compounds, such as flavonoids and alkaloids, have been shown to have strong effects against AD. Therefore, studying medicinal plants in depth and finding new active compounds against AD is necessary.

References

  • 1.

    Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006;368:387–403. CrossrefPubMedGoogle Scholar

  • 2.

    Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, et al. Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int 2010;57:547–55. CrossrefPubMedGoogle Scholar

  • 3.

    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–6. PubMedCrossrefGoogle Scholar

  • 4.

    Chun W, Johnson G. The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci 2006;12:733–56. Google Scholar

  • 5.

    Marchbanks R. Biochemistry of Alzheimer’s dementia. J Neurochem 1982;39:9–15. CrossrefPubMedGoogle Scholar

  • 6.

    Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 1999;66:137–47. CrossrefPubMedGoogle Scholar

  • 7.

    Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ. Choline acetyltransferase activity and cognitive domain scores of Alzheimer’s patients. Neurobiol Aging 2000;21:11–7. PubMedCrossrefGoogle Scholar

  • 8.

    McGleenon B, Dynan K, Passmore A. Acetylcholinesterase inhibitors in Alzheimer’s disease. Br J Clin Pharmacol 1999;48:471–80. PubMedGoogle Scholar

  • 9.

    Upadhyaya P, Seth V, Ahmad M. Therapy of Alzheimer’s disease: an update. Afr J Pharm Pharmacol 2010;4:408–21. Google Scholar

  • 10.

    Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. J Am Med Assoc 1994;271:992–8. CrossrefGoogle Scholar

  • 11.

    Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 2006;65:631–41. PubMedCrossrefGoogle Scholar

  • 12.

    Harman D. The aging process. Proc Natl Acad Sci 1981;78:7124–8. CrossrefGoogle Scholar

  • 13.

    Jung HA, Min B-S, Yokozawa T, Lee J-H, Kim YS, Choi JS. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull 2009;32:1433–8. PubMedCrossrefGoogle Scholar

  • 14.

    Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev 1994;74:139–62. PubMedGoogle Scholar

  • 15.

    Lovell MA, Markesbery WR. Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 2007;35:7497–504. PubMedCrossrefGoogle Scholar

  • 16.

    Grundman M, Delaney P. Antioxidant strategies for Alzheimer’s disease. Proc Nutr Soc 2002;61:191–202. CrossrefPubMedGoogle Scholar

  • 17.

    Staehelin HB. Micronutrients and Alzheimer’s disease. Proc Nutr Soc 2005;64:565v70. Google Scholar

  • 18.

    Lu P, Mamiya T, Lu L, Mouri A, Zou L, Nagai T, et al. Silibinin prevents amyloid β peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 2009;157:1270–7. PubMedCrossrefGoogle Scholar

  • 19.

    Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991;12:383–8. PubMedCrossrefGoogle Scholar

  • 20.

    Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–66. PubMedGoogle Scholar

  • 21.

    Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009;457:981–9. CrossrefPubMedGoogle Scholar

  • 22.

    West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 1994;344:769–72. PubMedCrossrefGoogle Scholar

  • 23.

    Martín S, González-Burgos E, Carretero ME, Gómez-Serranillos MP. Neuroprotective properties of Spanish red wine and its isolated polyphenols on astrocytes. Food Chem 2011;128:40–8. PubMedCrossrefGoogle Scholar

  • 24.

    Moreira PI, Honda K, Liu Q, Aliev G, Oliveira CR, Santos MS, et al. Alzheimer’s disease and oxidative stress: the old problem remains unsolved. Curr Med Chem-Cent Nerv Syst Agents 2005;5:51–62. CrossrefGoogle Scholar

  • 25.

    Bush AI. Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimer’s Dis 2008;15:223–40. CrossrefGoogle Scholar

  • 26.

    Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimer’s Dis 2010;20:509–16. CrossrefGoogle Scholar

  • 27.

    Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in neuroinflammation and Alzheimer’s disease. Curr Drug Targets 2004;5:529–34. CrossrefPubMedGoogle Scholar

  • 28.

    Moore AH, O’Banion MK. Neuroinflammation and anti-inflammatory therapy for Alzheimer’s disease. Adv Drug Deliv Rev 2002;54:1627–56. PubMedCrossrefGoogle Scholar

  • 29.

    Gasparini L, Ongini E, Wenk G. Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease: old and new mechanisms of action. J Neurochem 2004;91:521–36. PubMedCrossrefGoogle Scholar

  • 30.

    Breitner JC. Inflammatory processes and antiinflammatory drugs in Alzheimer’s disease: a current appraisal. Neurobiol Aging 1996;17:789–94. CrossrefPubMedGoogle Scholar

  • 31.

    Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging 2015;32:139–47. PubMedCrossrefGoogle Scholar

  • 32.

    Howes MJR, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 2003;17:1–18. CrossrefPubMedGoogle Scholar

  • 33.

    Ansari N, Khodagholi F. Natural products as promising drug candidates for the treatment of Alzheimer’s disease: molecular mechanism aspect. Curr Neuropharmacol 2013;11:414–29. PubMedCrossrefGoogle Scholar

  • 34.

    Olajide OJ, Yawson EO, Gbadamosi IT, Arogundade TT, Lambe E, Obasi K, et al. Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer’s disease. Environ Toxicol Pharmacol 2017;50:200–11. CrossrefPubMedGoogle Scholar

  • 35.

    D’Onofrio G, Sancarlo D, Ruan Q, Yu Z, Panza F, Daniele A, et al. Phytochemicals in the treatment of Alzheimer’s disease: a systematic review. Curr Drug Targets 2016;17. DOI: 10.2174/1389450117666161102121553. Google Scholar

  • 36.

    Ataie A, Shadifar M, Ataee R. Polyphenolic antioxidants and neuronal regeneration. Basic Clin Neurosci 2016;7:81–90. PubMedGoogle Scholar

  • 37.

    Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. The molecular targets and therapeutic uses of curcumin in health and disease. USA: Springer Science & Business Media, 2007:1–75. Google Scholar

  • 38.

    Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharm Exp Ther 2008;326:196–208. CrossrefGoogle Scholar

  • 39.

    Carvalho AC, Gomes AC, Pereira-Wilson C, Lima CF. Chapter 35 – mechanisms of action of curcumin on aging: nutritional and pharmacological applications A2 – Malavolta, Marco. In: Mocchegiani E, editor. Molecular basis of nutrition and aging. San Diego: Academic Press, 2016:491–511. Google Scholar

  • 40.

    Jiang S, Han J, Li T, Xin Z, Ma Z, Di W, et al. Curcumin as a potential protective compound against cardiac diseases. Pharmacol Res 2017;119:373–83. CrossrefPubMedGoogle Scholar

  • 41.

    Hamaguchi T, Ono K, Yamada M. Review: curcumin and Alzheimer’s disease. CNS Neurosci Ther 2010;16:285–97. CrossrefPubMedGoogle Scholar

  • 42.

    Veldman ER, Jia Z, Halldin C, Svedberg MM. Amyloid binding properties of curcumin analogues in Alzheimer’s disease postmortem brain tissue. Neurosci Lett 2016;630:183–8. CrossrefPubMedGoogle Scholar

  • 43.

    Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M. Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. Biomed Pharmacother 2017;87:721–40. CrossrefPubMedGoogle Scholar

  • 44.

    Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370–7. Google Scholar

  • 45.

    Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005;280:5892–901. CrossrefPubMedGoogle Scholar

  • 46.

    Butterfield D, Castegna A, Pocernich C, Drake J, Scapagnini G, Calabrese V. Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutritional Biochem 2002;13:444. CrossrefGoogle Scholar

  • 47.

    Sahu PK. Design, structure activity relationship, cytotoxicity and evaluation of antioxidant activity of curcumin derivatives/analogues. Eur J Med Chem 2016;121:510–6. CrossrefPubMedGoogle Scholar

  • 48.

    DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J 2012;11:79. PubMedCrossrefGoogle Scholar

  • 49.

    Gohil K, Patel J. A review on Bacopa monniera: current research and future prospects. Int J Green Pharm 2010;4:1. CrossrefGoogle Scholar

  • 50.

    Russo A, Borrelli F. Bacopa monniera, a reputed nootropic plant: an overview. Phytomedicine 2005;12:305–17. PubMedCrossrefGoogle Scholar

  • 51.

    Dhanasekaran M, Tharakan B, Holcomb LA, Hitt AR, Young KA, Manyam BV. Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera. Phytother Res 2007;21:965–9. CrossrefPubMedGoogle Scholar

  • 52.

    MS Bharath M. Exploring the role of “Brahmi” (Bocopa monnieri and Centella asiatica) in brain function and therapy. Recent Pat Endocr Metab Immune Drug Discov 2011;5:33–49. CrossrefPubMedGoogle Scholar

  • 53.

    Singh H, Dhawan B. Effect of Bacopa monniera Linn. (Brāhmi) extract on avoidance responses in rat. J Ethnopharmacol 1982;5:205–14. PubMedCrossrefGoogle Scholar

  • 54.

    Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol 2010;127:26–31. PubMedCrossrefGoogle Scholar

  • 55.

    Bhattacharya S, Bhattacharya A, Kumar A, Ghosal S. Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus. Phytother Res 2000;14:174–9. PubMedCrossrefGoogle Scholar

  • 56.

    Limpeanchob N, Jaipan S, Rattanakaruna S, Phrompittayarat W, Ingkaninan K. Neuroprotective effect of Bacopa monnieri on beta-amyloid-induced cell death in primary cortical culture. J Ethnopharmacol 2008;120:112–7. PubMedCrossrefGoogle Scholar

  • 57.

    Sadhu A, Upadhyay P, Agrawal A, Ilango K, Karmakar D, Singh GP, et al. Management of cognitive determinants in senile dementia of Alzheimer’s type: therapeutic potential of a novel polyherbal drug product. Clin Drug Investig 2014;34:857–69. CrossrefPubMedGoogle Scholar

  • 58.

    Sethiya NK, Nahata A, Mishra SH, Dixit VK. An update on Shankhpushpi, a cognition-boosting Ayurvedic medicine. Zhong Xi Yi Jie He Xue Bao 2009;7:1001–22. PubMedCrossrefGoogle Scholar

  • 59.

    Malik J, Karan M, Vasisht K. Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi. Pharm Biol 2011;49:1234–42. PubMedCrossrefGoogle Scholar

  • 60.

    Nahata A, Patil U, Dixit V. Effect of Convulvulus pluricaulis Choisy. on learning behaviour and memory enhancement activity in rodents. Nat Prod Res 2008;22:1472–82. CrossrefPubMedGoogle Scholar

  • 61.

    Bihaqi SW, Singh AP, Tiwari M. Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and Amyloid precursor protein (AβPP) expression in rat brain. Indian J Pharmacol 2012;44:593. PubMedCrossrefGoogle Scholar

  • 62.

    Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol 2003;30:336–42. CrossrefGoogle Scholar

  • 63.

    Chen C-L, Tsai W-H, Chen C-J, Pan T-M. Centella asiatica extract protects against amyloid β 1–40-induced neurotoxicity in neuronal cells by activating the antioxidative defence system. J Tradit Complement Med 2016;6:362–9. CrossrefGoogle Scholar

  • 64.

    Dhanasekaran M, Holcomb LA, Hitt AR, Tharakan B, Porter JW, Young KA, et al. Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer’s disease animal model. Phytother Res 2009;23:14–9. CrossrefPubMedGoogle Scholar

  • 65.

    Defeudis FV. Bilobalide and neuroprotection. Pharmacol Res 2002;46:565–8. PubMedCrossrefGoogle Scholar

  • 66.

    Zhou L-J, Zhu X-Z. Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharm Exp Ther 2000;293:982–8. Google Scholar

  • 67.

    Tchantchou F, Lacor PN, Cao Z, Lao L, Hou Y, Cui C, et al. Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons. J Alzheimers Dis 2009;18:787–98. CrossrefPubMedGoogle Scholar

  • 68.

    Yakoot M, Salem A, Helmy S. Effect of Memo®, a natural formula combination, on Mini-Mental State Examination scores in patients with mild cognitive impairment. Clin Interv Aging 2013;8:975–81. Google Scholar

  • 69.

    Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol 2008;46:409–20. CrossrefGoogle Scholar

  • 70.

    Oboh G, Ademiluyi AO, Akinyemi AJ. Inhibition of acetylcholinesterase activities and some pro-oxidant induced lipid peroxidation in rat brain by two varieties of ginger (Zingiber officinale). Exp Toxicol Pathol 2012;64:315–9. CrossrefPubMedGoogle Scholar

  • 71.

    Essa MM, Vijayan RK, Castellano-Gonzalez G, Memon MA, Braidy N, Guillemin GJ. Neuroprotective effect of natural products against Alzheimer’s disease. Neurochem Res 2012;37:1829–42. PubMedCrossrefGoogle Scholar

  • 72.

    Borek C. Antioxidant health effects of aged garlic extract. J Nutr 2001;131:1010S–5S. Google Scholar

  • 73.

    Borek C. Garlic reduces dementia and heart-disease risk. J Nutr 2006;136:810S–2S. Google Scholar

  • 74.

    Nillert N, Pannangrong W, Welbat JU, Chaijaroonkhanarak W, Sripanidkulchai K, Sripanidkulchai B. Neuroprotective effects of aged garlic extract on cognitive dysfunction and neuroinflammation induced by β-amyloid in rats. Nutrients 2017;9:24. CrossrefGoogle Scholar

  • 75.

    Qu Z, Mossine VV, Cui J, Sun GY, Gu Z. Protective effects of AGE and its components on neuroinflammation and neurodegeneration. Neuromol Med 2016;18:474–82. CrossrefGoogle Scholar

  • 76.

    Ossola B, Kääriäinen TM, Männistö PT. The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 2009;8:397–409. CrossrefPubMedGoogle Scholar

  • 77.

    Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol 2012;83:6–15. PubMedCrossrefGoogle Scholar

  • 78.

    Bischoff SC. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care 2008;11:733–40. PubMedCrossrefGoogle Scholar

  • 79.

    Jiménez-Aliaga K, Bermejo-Bescós P, Benedí J, Martín-Aragón S. Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells. Life Sci 2011;89:939–45. PubMedCrossrefGoogle Scholar

  • 80.

    Ansari MA, Abdul HM, Joshi G, Opii WO, Butterfield DA. Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer’s disease. J Nutr Biochem 2009;20:269–75. PubMedCrossrefGoogle Scholar

  • 81.

    Puerta E, Suárez-Santiago JE, Santos-Magalhães NS, Ramirez MJ, Irache JM. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int J Pharm 2017;517:50–7. CrossrefPubMedGoogle Scholar

  • 82.

    Ahmad N, Feyes DK, Agarwal R, Mukhtar H, Nieminen A-L. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Ins 1997;89:1881–6. CrossrefGoogle Scholar

  • 83.

    Biasibetti R, Tramontina AC, Costa AP, Dutra MF, Quincozes-Santos A, Nardin P, et al. Green tea (−) epigallocatechin-3-gallate reverses oxidative stress and reduces acetylcholinesterase activity in a streptozotocin-induced model of dementia. Behav Brain Res 2013;236:186–93. CrossrefGoogle Scholar

  • 84.

    Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, et al. Green tea (-)-epigallocatechin-3-gallate inhibits β-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-κB pathways in mice. J Nutr 2009;139:1987–93. CrossrefPubMedGoogle Scholar

  • 85.

    Li R, Huang YG, Fang D, Le WD. (−)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res 2004;78:723–31. PubMedCrossrefGoogle Scholar

  • 86.

    Lee Y-J, Choi D-Y, Yun Y-P, Han SB, Oh K-W, Hong JT. Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties. J Nutr Biochem 2013;24:298–310. CrossrefPubMedGoogle Scholar

  • 87.

    Chang X, Rong C, Chen Y, Yang C, Hu Q, Mo Y, et al. (−)-Epigallocatechin-3-gallate attenuates cognitive deterioration in Alzheimer’s disease model mice by upregulating neprilysin expression. Exp Cell Res 2015;334:136–45. PubMedCrossrefGoogle Scholar

  • 88.

    Kulkarni S, Dhir A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 2010;24:317–24. CrossrefPubMedGoogle Scholar

  • 89.

    Durairajan SS, Liu L-F, Lu J-H, Chen L-L, Yuan Q, Chung SK, et al. Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol Aging 2012;33:2903–19. CrossrefGoogle Scholar

  • 90.

    Zhu F, Qian C. Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer’s disease. BMC Neurosci 2006;7:78. PubMedCrossrefGoogle Scholar

  • 91.

    Jia L, Liu J, Song Z, Pan X, Chen L, Cui X, et al. Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. J Pharm Pharmacol 2012;64:1510–21. CrossrefPubMedGoogle Scholar

  • 92.

    Huang M, Jiang X, Liang Y, Liu Q, Chen S, Guo Y. Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of β-amyloid in APP/tau/PS1 mouse model of Alzheimer’s disease. Exp Gerontol 2017;91:25–33. PubMedCrossrefGoogle Scholar

  • 93.

    de Oliveira JS, Abdalla FH, Dornelles GL, Adefegha SA, Palma TV, Signor C, et al. Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death. NeuroToxicol 2016;57:241–50. CrossrefGoogle Scholar

  • 94.

    Bhat KP, Kosmeder JW, Pezzuto JM. Biological effects of resveratrol. Antioxid Redox Signal 2001;3:1041–64. CrossrefPubMedGoogle Scholar

  • 95.

    Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for Alzheimer’s disease. Curr Pharm Des 2012;18:27–33. CrossrefPubMedGoogle Scholar

  • 96.

    Kumar A, Naidu P, Seghal N, Padi S. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology 2006;79:17–26. PubMedCrossrefGoogle Scholar

  • 97.

    Luo L, Huang YM. [Effect of resveratrol on the cognitive ability of Alzheimeros mice]. Zhong Nan Da Xue Xue Bao. Yi Xue Ban J Centr South University. Med Sci 2006;31:566–9. Google Scholar

  • 98.

    Turner RS, Thomas RG, Craft S, Van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 2015;85:1383–91. PubMedCrossrefGoogle Scholar

  • 99.

    He X, Li Z, Rizak JD, Wu S, Wang Z, He R, et al. Resveratrol attenuates formaldehyde induced hyperphosphorylation of tau protein and cytotoxicity in N2a cells. Front Neurosci 2017;10:598. PubMedGoogle Scholar

  • 100.

    Karthick C, Periyasamy S, Jayachandran KS, Anusuyadevi M. Intrahippocampal administration of ibotenic acid induced cholinergic dysfunction via NR2A/NR2B expression: implications of resveratrol against Alzheimer disease pathophysiology. Front Mol Neurosci 2016;9:28. PubMedGoogle Scholar

  • 101.

    Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflamm 2017;14:1. CrossrefGoogle Scholar

  • 102.

    Ha GT, Wong RK, Zhang Y. Huperzine a as potential treatment of Alzheimer’s disease: an assessment on chemistry, pharmacology, and clinical studies. Chem Biodivers 2011;8:1189–204. CrossrefPubMedGoogle Scholar

  • 103.

    Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero D, Perez B, Clos M, et al. Huprine X and huperzine A improve cognition and regulate some neurochemical processes related with Alzheimer’s disease in triple transgenic mice (3xTg-AD). Neurodegener Dis 2012;11:129–40. PubMedGoogle Scholar

  • 104.

    Zhang HY, Tang XC. Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci 2006;27:619–25. PubMedCrossrefGoogle Scholar

  • 105.

    Wang Y, Tang XC, Zhang HY. Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice. J Neurosci Res 2012;90:508–17. CrossrefPubMedGoogle Scholar

  • 106.

    Wang C-Y, Zheng W, Wang T, Xie J-W, Wang S-L, Zhao B-L, et al. Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model. Neuropsychopharmacology 2011;36:1073–89. CrossrefGoogle Scholar

  • 107.

    Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP, Ved HS. The NMDA receptor ion channel: a site for binding of Huperzine A. J Appl Toxicol 2001;21(S1):S47–51. CrossrefPubMedGoogle Scholar

  • 108.

    Rafii M, Walsh S, Little JT, Behan K, Reynolds B, Ward C, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology 2011;76:1389–94. PubMedCrossrefGoogle Scholar

  • 109.

    Shekarchi M, Hajimehdipoor H, Saeidnia S, Gohari AR, Hamedani MP. Comparative study of rosmarinic acid content in some plants of Labiatae family. Pharmacogn Mag 2012;8:37–41. CrossrefPubMedGoogle Scholar

  • 110.

    Petersen M, Simmonds MS. Rosmarinic acid. Phytochemistry 2003;62:121–5. CrossrefPubMedGoogle Scholar

  • 111.

    Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Aβ 25–35. Behav Brain Res 2007;180:139–45. PubMedCrossrefGoogle Scholar

  • 112.

    Iuvone T, De Filippis D, Esposito G, D’Amico A, Izzo AA. The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-β peptide-induced neurotoxicity. J Pharm Exp Ther 2006;317:1143–9. CrossrefGoogle Scholar

  • 113.

    Gok DK, Ozturk N, Er H, Aslan M, Demir N, Derin N, et al. Effects of rosmarinic acid on cognitive and biochemical alterations in ovariectomized rats treated with D-galactose. Folia Histochem Cyto 2015;53:283–93. Google Scholar

  • 114.

    Lopez-Lazaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 2009;9:31–59. CrossrefPubMedGoogle Scholar

  • 115.

    Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 2008;74:1667–77. CrossrefPubMedGoogle Scholar

  • 116.

    Zhou F, Chen S, Xiong J, Li Y, Qu L. Luteolin reduces zinc-induced tau phosphorylation at Ser262/356 in an ROS-dependent manner in SH-SY5Y cells. Biol Trace Elem Res 2012;149:273–9. CrossrefGoogle Scholar

  • 117.

    Liu R, Meng F, Zhang L, Liu A, Qin H, Lan X, et al. Luteolin isolated from the medicinal plant Elsholtzia rugulosa (Labiatae) prevents copper-mediated toxicity in β-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells. Molecules 2011;16:2084–96. PubMedCrossrefGoogle Scholar

  • 118.

    Hwang Y-J, Lee E-J, Kim H-R, Hwang K-A. Molecular mechanisms of luteolin-7-O-glucoside-induced growth inhibition on human liver cancer cells: G2/M cell cycle arrest and caspase-independent apoptotic signaling pathways. BMB Rep 2013;46:611–6. PubMedCrossrefGoogle Scholar

  • 119.

    Fu X, Zhang J, Guo L, Xu Y, Sun L, Wang S, et al. Protective role of luteolin against cognitive dysfunction induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav 2014;126:122–30. CrossrefPubMedGoogle Scholar

  • 120.

    Wang H, Wang H, Cheng H, Che Z. Ameliorating effect of luteolin on memory impairment in an Alzheimer’s disease model. Mol Med Rep 2016;13:4215–20. CrossrefGoogle Scholar

About the article

Received: 2016-09-27

Accepted: 2017-05-28

Published Online: 2017-07-14

Published in Print: 2017-09-26


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved its submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, Volume 28, Issue 5, Pages 413–423, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2016-0147.

Export Citation

©2017 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Juan Ángel Carrillo, M Pilar Zafrilla, and Javier Marhuenda
Foods, 2019, Volume 8, Number 10, Page 507
[2]
Angela De Simone, Marina Naldi, Daniele Tedesco, Manuela Bartolini, Lara Davani, and Vincenza Andrisan
Journal of Pharmaceutical and Biomedical Analysis, 2019, Page 112899
[3]
Aimi Syamima Abdul Manap, Amelia Cheng Wei Tan, Weng Hhin Leong, Adeline Yoke Yin Chia, Shantini Vijayabalan, Aditya Arya, Eng Hwa Wong, Farzana Rizwan, Umesh Bindal, Shajan Koshy, and Priya Madhavan
Frontiers in Aging Neuroscience, 2019, Volume 11
[4]
Jia Xu, Kai Wang, Ye Yuan, Hui Li, Ruining Zhang, Shuwen Guan, and Liping Wang
International Journal of Molecular Sciences, 2018, Volume 19, Number 11, Page 3304
[5]
Fatemeh Babaei, Mohammadreza Mirzababaei, and Marjan Nassiri-Asl
Journal of Food Science, 2018
[6]
Geir Bjørklund, Maryam Dadar, Salvatore Chirumbolo, and Roman Lysiuk
Food and Chemical Toxicology, 2017
[7]

Comments (0)

Please log in or register to comment.
Log in