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Introduction
Since the discovery of Alzheimer's disease (AD) in 1907,
considerable effort has been devoted to combating the
disease. However, up to now, there is no effective
thera-peutics. With the accelerated aging of human society, AD is
becoming one of the biggest threats to human
health[1_3]. Although the etiology of AD is not very clear, multiple
pathogenetic factors have been identified for the disease, which
include amyloid-β (Aβ) peptide and/or τ protein aggregation,
excessive metal ions (eg, Cu2+,
Zn2+, Fe3+), oxidative stress
and reduced acetylcholine (ACh) level,
etc[1_8]. Besides, genetic factors and lifestyles, such as diet, exercise and cognitive
stimulation, are also associated with AD
development[9,10].
Despite the diverse pathogenetic factors involved in AD,
the current anti-AD strategy depends largely on
single-targeted drugs, especially acetylcholinesterase (AChE)
inhibitors. As these drugs' effects are quite
limited[11], more and more attention is given to fin d multiple-targeted agents
to hit more than one target implicated in
AD[12,13]. Although the new anti-AD strategy may be fulfilled by combining
different anti-AD drugs in one pill (cocktail
therapeutics)[14,15], an alternative approach that aims at multiple AD-targets with
a single structure (termed multipotent agent) is also attractive,
because of its advantages in reducing risks of drug-drug
interactions and controlling pharmacokinetic
behaviors[15].
Thanks to the continuing effort of medicinal chemists in
the past decade, many multipotent anti-AD agents have been
rationally designed by incorporating two or more
pharma-cophores in one scaffold, in which the pharmacophores for
inhibiting AChE were most widely
used[12,13]. For instance, Rosini et
al[16] designed a hybrid compound (lipocrine)
(Figure 1) by linking tacrine, an AChE inhibitor, and lipoic acid, a
universal antioxidant. Rodríguez-Franco
et al coupled tacrine to melatonin, a pineal neurohormone and a preventive
antioxidant (Figure 1)[17]. These hybrid molecules exhibited
markedly enhanced activity with respect to AChE inhibition and
antioxidant properties compared with either of the original
molecules[16,17]. By joining together the pharmaco-phores
for inhibiting AChE and monoamine oxidases B (MAO-B),
ie, carbamate and propargyl group, Sterling
et al[18] also obtained novel dual inhibitors of AChE and MAO.
Despite the preliminary successes of synthetic hybrid
agents, the latent risks in safety and bioavailability is a big
concern in their further development. Thus, finding
multipotent natural agents to combat AD is attracting more and more
attention.
Multipotent anti-AD agents derived from foods
In the past few years, some epidemiological investigations
revealed that high consumption of some foods (or beverages)
were inversely associated with AD
incidence[19_25]. These foods include fruit and vegetable juices, green tea, wine,
Mediterranean diet, curry spice turmeric and even cigarettes,
all of which contain antioxidants, especially polyphenols.
As it is well known that polyphenols are excellent
antioxidants both as reactive oxygen species (ROS) scavengers and
transition metal chelators[26,27], the anti-AD effects of these
foods were naturally linked to their antioxidant potential.
Nevertheless, accumulating evidence indicates that the
excellent in vitro antioxidant activity of phenols can not
necessarily be translated into in vivo therapeutic
effects[28,29]. Thus, it is interesting to note that some antioxidants derived from
these foods go beyond modulating ROS. Some
representative examples are given as below.
Flavonoids Flavonoids are the most extensively studied
polyphenols derived from fruit and vegetable juices and green
tea. Multiple pharmacological effects have been identified
for flavonoids, many of which are beneficial to combat AD.
For instance, quercetin (Figure 2), the representative
component of fruit and vegetable juices, can block
Aβ- or τ-aggregation (IC50s < 1
µmol/L)[30], inhibit monoamine oxidases
A and B (MAO A and MAO B) with IC50s of 0.01 µmol/L and
10.89 µmol/L, respectively[31,32]. In addition, quercetin can
efficiently inhibit butyrylcholinesterase (BChE) (with an
IC50 of 1 µmol/L)[33], a recently recognized potential target for
treating AD[34]. As quercetin is highly bioavailable and can
pass through the blood-brain barrier
(BBB)[35,36], it seems partially responsible for the benefits of fruit and vegetable
juices to AD.
(-)-Epigallocatechin gallate (EGCG) (Figure 2) is the
representative component of green tea. Some potential
anti-AD effects of EGCG have been identified as follows: i) it is
a powerful Aβ-aggregation inhibitor with an
IC50 of 0.18 µmol/L[30]; ii) it attenuates
Aβ generation through activating
a-secretase[37,38], inhibiting β-secretase (BACE1, with an
IC50 of 1.6 µmol/L)[39] and reducing iron-regulated amyloid
precursor protein expression[40]; iii) it inhibits MAO with an
IC50 of 10 µmol/L[41]. All of these pharmacological effects are
helpful to understand the preventive effects of green tea to
AD.
Resveratrol Resveratrol (Figure 2) is a famous phenolic
component extracted from red wine, which has been
extensively studied in the past 15 years. Some pharmacological
effects that are associated with AD treatment have been
revealed. First, resveratrol can lower the levels of secreted
and intracellular Aβ by promoting protease degradation of
the peptide[42]. Second, resveratrol inhibits monoamine
oxidase A (MAO-A) with an IC50 of 26.6
µmol/L[43]. Third, resveratrol can inhibit cyclooxygenase-1 (COX-1) with an
IC50 of 24 µmol/L[44] and reduce cyclooxygenase-2 (COX-2)
at mRNA level[45].
Olive oil phenols Mediterranean diet consists of olive
oil, fruits, vegetables and fish, of which olive oil is of special
interest and has been a research focus for decades. Many
phenolic compounds have been identified from olive
oil[46], some of which exhibit nonsteroidal anti-inflammatory
drug-like activities that are beneficial to prevent AD. For
instance, Beauchamp et al revealed that 25 µmol/L (-)-oleocanthal
(Figure 2) inhibited 56.1%±3.2% and
56.6%±9.5% COX-1 and COX-2 activity,
respectively[47]. In addition, Bazoti
et al found that oleuropein (Figure 2) can form noncovalent
complex with Aβ peptide or its oxidized
form[48].
Curcumin Curcumin (Figure 2), a yellow-orange
pigment extracted from curry spice turmeric, has long been used
as a food additive in India. Many pharmacological effects
have been identified for this
pigment[49]. Besides its famous transition metal-chelating ability and anti-inflammatory
activity[50_52], curcumin holds Aβ aggregation-blocking
potential (with an IC50 of < 1
µmol/L)[30] and COX-1-,
COX-2-inhibiting activities (with IC50s of 18.8 µmol/L and 15.9± 7.9
µmol/L, respectively).[53,54]
Nicotine Nicotine (Figure 2) is the predominant
component of cigarette smoke, which is considered responsible for
the cigarettes' benefits to AD. Recently, Zhao and co-workers
revealed that nicotine attenuated the β-amyloid neurotoxicity
through regulating metal (copper and zinc)
homeostasis[55] and activating nicotinic acetylcholine
receptors[56,57]. Combining experimental findings and theoretical calculation results, we
indicated that the copper(II)-nicotine chelates hold
SOD-like activity, which may play a role in the neuroprotective
effects of nicotine[58].
Multipotent anti-AD agents derived from herbs
It is not surprising to note that in addition to foods, some
herbal medicines, such as G Biloba, Huperzia
serrata, Salvia officinalis, Melissa
officinalis, also hold anti-AD potential, as revealed by some preliminary clinical
trials[59_64]. Some ingredients responsible for the anti-AD effects have been
identified from these herbs.
Extract EGb761 (extract G biloba 761), prepared from the
leaves of G biloba and comprising flavonoids and terpene
lactones, was a hot spot of medicinal research in the past
two decades. EGb761 has many pharmacological effects in
favor of the fight against AD, which include inhibiting
Aβ aggregation, attenuating apoptosis, preventing membrane
lipid from oxidation and resisting
inflammation[65].
Huperzine A (HupA) (Figure 3), an alkaloid isolated from
Chinese herb Huperzia serrata, is also a potent multipotent
anti-AD agent, with activities of inhibiting AChE (with an
IC50 of 0.082
µmol/L)[60], mitigating oxidative stress,
regulating the expression of apoptotic proteins Bcl-2, Bax, p53, and
caspase-3, interfering with amyloid precursor protein
metabolism and so on, which definitely benefits the
neuro-protection[60,61].
Rosmarinic acid (Figure 3) is likely to be one of the major
active ingredients of Salvia officinalis and
Melissa officinalis, which exhibits a combination of antioxidative,
anti-Aβ aggregation and antiapoptotic
effects[66].
Recently, xanthones, a special kind of flavonoids that
spread widely in nature, were also found possessing high
anti-AD potential. Indeed, some xanthone-containing herbs,
such as Polygala tenuifolia, show benefits to prevent
AD[67]. A representative of multipotent anti-AD xanthone is
presented in Figure 3. It can inhibit MAO-A (with
an IC50 of 0.04 µmol/L), MAO-B (with an
IC50 of 33.0 μmol/L) and AChE (with a
Ki of 16.0
µmol/L)[68,69]. Because of the perfect conjugation
of the ring system and the electron-withdrawing property of
1,4-pyrone (the central ring)[70,71], xanthones are weaker
electron donors than flavonoids[72], which implies that xanthones
are safer than flavonoids with respect to the prooxidant
potential.
Structural features of naturally occurring multipotent anti-AD agents
From the structures of rational designed and naturally
occurring multipotent anti-AD agents, it can be found that both
kinds of compounds are different in scaffold, that is, the latter
shows a seamless framework (Figures 2 and 3), while the former
is composed of two or more isolated parts, linked by spacers
of different lengths, with each part aiming at a particular target
(Figure 1). So, it is of significance to explore the natural
strategy of "designing" multipotent anti-AD agents.
Through examining the structures of above-mentioned
multipotent natural agents, we can find that most of them are
phenolics. It is well known that phenolic hydroxyls are the
most potent groups to neutralize ROS through donating
H-atoms[73] and also effective to chelate transition metal
ions[26]. However, the present description shows that natural
phenolics go beyond scavenging ROS or chelating transition
metals. They can inhibit various enzyme's activities and
prevent protein aggregation. The major underlying reason
may be that phenolic hydroxyls are H-bond acceptors and
H-bond donors simultaneously, which facilitates the
binding with protein targets. This explanation is supported by a
meta-analysis on phenol-protein binding patterns which
revealed that more than 70% phenolic hydroxyls form
intermolecular hydrogen bonds (IHBs) with targeted
proteins[28]. Another feature of the naturally occurring multipotent
anti-AD agents is that their structures contain more than one
conjugated rings (most are phenolic rings) and most of the
conjugated systems are still flexible. Thus, these molecules
reach a good balance between rigidity and flexibility, which
must benefit their binding with various targets. To illustrate
the importance of these structural features in binding
diverse target proteins, some multipotent agents were docked
with corresponding targets. As shown in Figures 4_8, the
phenolic hydroxyls indeed tend to form IHBs with
surrounding residues and the flexible structures favor the binding
between agents and proteins. Finally, since
p-stacking plays an important role in protein amyloid
formation[30,74], the aromaticity of phenolic ring is favorable to prohibit amyloid
fibril formation[75].
Conclusion
Thanks to the continuing efforts of medicinal chemists
and pharmacologists in the past decade, more and more
natural agents that can hit multiple targets implicated in AD (eg,
Aβ, τ protein, AChE, BChE, MAO, COX, α-, and β-secretases,
ROS and transition metals) were identified. As most of these
agents are bioavailable and can penetrate blood-brain
barrier (BBB) (at least in animal
models)[35,36,76_79], they are likely responsible for the AD-preventing effects of the source
plants, as revealed by epidemiological investigations and
preliminary clinical trials. Thus, these agents are good
starting points for finding novel anti-AD drugs. Through
examining the structures of these agents, it was revealed that
phenolics with certain flexibility are preferred by the
naturally occurring multipotent anti-AD agents, which has
important implications for screening and design of novel
multipotent anti-AD drugs.
Considering the fact that current knowledge about
natural products is very limited, we think that the presently
identified natural multifunctional agents are the tip of the iceberg.
With the increase of information on natural medicines, more
and more pleiotropic anti-AD compounds will be discovered
from medicinal plants in China and/or other geographical
regions.
The present analysis also has significance to find drugs
for other neurodegenerative diseases, such as prion diseases,
Parkinson's disease, and amyotrophic lateral sclerosis,
because these diseases are also characterized by progressive
neuronal loss and involve similar multiple pathogenetic
factors (eg, protein aggregation, transition metals and
excessive ROS)[5,6,76,80] and different types of soluble amyloid
oligomers bear a common structure[81].
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