Keywords

5.1 Beyond the Molecular Frontier – The Threats of Our Age

During the past hundred years, treatments for human diseases have helped raise life expectancy significantly. However, an aging population brings increased burdens and costs to individuals and society from age-related cognitive decline; indeed, the latter has emerged as one of the major health threats and challenges of our age. In another 36 years there will be triple the number of persons 80 years or older, with approximately 50 % of adults over 85 years afflicted with Alzheimer’s disease (AD). The total number of new cases of dementia each year worldwide is nearly 7.7 million, which translates to ~15 new cases every minute (International 2012). Estimates indicate that between 2 and 10 % of all cases of dementia appear before the age of 65. Advancing age is the highest risk factor for AD, with age-specific prevalence nearly doubling every 5 years beyond the age of 65. The financial estimated worldwide cost of dementia was $604 billion in 2010 (Wimo et al. 2013). Unless we act now, by 2050 the problem will be unmanageable. Recent advances in the biology of aging in model organisms, together with molecular and multidisciplinary studies of neurodegenerative and aging-related disease risks and personal practices (outlined in Scheme 5.1), are beginning to uncover these mechanisms and their potential roles in cognitive decline (Witte et al. 2009; Villeda et al. 2011)

Scheme 5.1
scheme 1

The interventions and disease risks related to Alzheimer’s disease

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Interrelationships between aging, apolipoprotein E (APOE) ε4 allele, oxidative damage, reactive oxygen species (ROS), amyloid metabolism/toxicity and neurodegenerative dysfunctions leading to dementia and AD are highly probable. Nevertheless, the precise mechanisms remain unknown. Ideally, the opportunities for making lifestyle, diet and nutritional choices to enhance human brain and body function is available and practiced by many (Gomez-Pinilla and Tyagi 2013). The theme of positive aging is to be proactive in minimizing/preventing cognitive decline and disease. Dementia and AD research priorities have also advanced from simply considering clinical symptoms. The focus is now more on early detection of the pre-symptomatic phase and the prevalence of early dementia signs, as these are considered to be potential windows of opportunity for successful therapeutic interventions and preventions. For instance, recent research supports mounting evidence implicating dysfunctional lipid metabolism in the pathophysiology of AD indicating that lipid biomarkers have the potential to predict memory impairment at a preclinical stage of AD. Changes in the blood profile of a set of ten lipids critical for proper cell membrane structure and function in elderly persons who showed no signs of cognitive problems, predicted they would go on to develop either mild memory impairment or AD within 2–3 years, with greater than 90 % accuracy (Mapstone et al. 2014).

Humans are able to consume a vast range of foodstuffs. However, the ready availability and low cost of food, and the freedom of being able to eat anything, does not mean that we should maximize eating practices to eat everything (Ulijaszek et al. 2012). The diet-related chronic diseases of modern society are now the single largest cause of death encompassing diabetes, cardiovascular disease, hypertension, obesity and cognitive decline (Scheme 5.1). For foods to promote the health of our aging, physical frailty and mental state, we need to reduce the consumption of processed foods and fatty diets, with negative nutritional attributes such as high-energy refined sugars, saturated fats and high sodium content, whilst increasing affinity and tendency to consume those with positive health attributes including phytochemicals and micronutrient rich foods.

5.2 Herbal Polyphenols – Modulation of Oxidative Stress, Dementia and AD

From our previous analysis of well-designed, randomized double-blind controlled trials on Chinese herbal medicines beneficial for the improvement of cognitive function, we found that neuroprotective benefits of suppression of oxidative stress as the most common feature provided by single herbs or herbal mixtures (May et al. 2009, 2012).

5.2.1 Epigallocatechin-3-Gallate

Oxidative stress may directly initiate neurodegeneration, and herbal antioxidant neuroprotection is considered as a preventative and therapeutic approach (Hugel et al. 2012). Crucially, the scientific evidence confirms that the majority of herbal polyphenolic compounds have a good safety profile, are affordable and are globally readily available to significantly reduce the burden of dementia and AD.

It has been known for at least a decade that polyphenols possess anti-amyloidogenic activity. A diverse range of herbal polyphenolic constituents including tannic acid, quercetin, kaempferol, curcumin, catechin and epicatechin are known to dose-dependently inhibit the formation of amyloid-beta (Aβ) fibrils as well as their elongation. Importantly, polyphenols can bind directly to Aβ or mature aggregates and impair their stability. Epigallocatechin-3-gallate (EGCG), a major component of green tea, significantly inhibits Aβ aggregation and has the ability to remodel large Aβ fibrils into smaller aggregates that are non-toxic (Wang et al. 2010). The gallate functionality in EGCG is critical in facilitating the reduction of Aβ and increasing APP α-proteolysis. Evidence has indicated that EGCG reduces Aβ production in both neuronal and mouse AD models in concert with activation of anti-amyloidogenic amyloid precursor protein (APP) α-processing. An extensive screening of the effect of other gallate-containing phenolic compounds on APP anti-amyloidogenic processing found that long chain gallate esters (Zhang et al. 2013b) such as octyl gallate (OG; 10 mM), a commercial food antioxidant, drastically decreased Aβ generation, in concert with increased APPα-proteolysis in murine neuron-like cells transfected with human wild-type APP or “Swedish” mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). OG increases anti-amyloidogenic APPα-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10. Fish oil has been shown to have a synergistic effect in combination with EGCG, with co-treatment leading to a reduction in Aβ plaque formation and levels of Aβ(1–40) and Aβ(1–42) in AD transgenic Tg2576 mice (Giunta et al. 2010). The potential role of polyphenols in neurodegeneration and the pathogenesis of AD has expanded with discoveries that they can modulate a class of proteins called sirtuins that are involved in longevity and cell survival (Jayasena et al. 2013) (Table 5.1).

Table 5.1 Anti-amyloidogenic activity of polyphenols and herbal extracts
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EGCG has numerous health-promoting effects (Hugel and Jackson 2012) including anti-cancer, antioxidant, anti-inflammatory, anti-diabetic, anti-aging and in particular its Aβ-sheet disruption (Palhano et al. 2013) capacity (outlined in Scheme 5.2). The major research challenge concerning the anti-amyloidogenic benefits of polyphenol-containing herbs and foods is to enhance their bioavailability and brain permeability (Schaffer and Halliwell 2012; Singh et al. 2008; Green et al. 2007; Lambert et al. 2006; Smith et al. 2010; van Duynhoven et al. 2011). Furthermore, the bioavailability of polyphenols from dietary input is highly variable between individuals and generally far too low to explain their bioactive antioxidant effects in vivo (Lotito and Frei 2006).

Scheme 5.2
scheme 2

The multiple therapeutic applications of green tea constituent EGCG

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5.2.2 Curcumin

Cur is a promising neuroprotective anti-AD natural product that however has poor brain bioavailability with incompletely defined therapeutic mechanisms. Its antioxidant, anti-inflammatory properties have been extensively documented (Esatbeyoglu et al. 2012; Wang et al. 2014). Cur-nanoparticles with improved brain permeability induced adult neurogenesis through activation of the canonical Wnt/β-catenin pathway, and may provide opportunities for treating AD by enhancing a brain self repair mechanism (Zhang et al. 2013c).

5.2.3 Magnolia officinalis

The herbal constituents shown in Fig. 5.1 from Magnolia officinalis and other members of the Magnoliaceae family have diverse therapeutic applications (Lee et al. 2011b). The neolignan 4-O-methylhonokiol is a potent cannabinoid receptor type-2 (CB2) ligand and has been found to attenuate memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the extracellular signal-regulated kinase (ERK) pathway (Lee et al. 2011a). The various neuroprotective and anti-Alzheimer disease effects reported in rodent models (Lee et al. 2011a) may be mediated via CB2 receptors, providing evidence that the compound should be bioavailable in the brain.

Fig. 5.1
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Major bioactive constituents found in Magnolia officinalis

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5.2.4 Annona glabrais – Squamosamide Derivative (FLZ Compound)

Traditional Chinese medicine makes use of several constituents from the leaves and roots of Annona glabrais, including a natural squamosamide. Importantly, the squamosamide derivative FLZ showed enhanced antioxidant activity; in APP-SH-SY5Y expressing cells it selectively inhibited γ-secretase activity without modulating the Notch pathway (Ye et al. 2014). The many positive anti-amyloidogenic studies suggest FLZ may have therapeutic potential for the treatment of AD (illustrated in Scheme 5.3) (Fang et al. 2012; Kang and Zhang 2012; Pang et al. 2009; Li and Liu 2010; Kong et al. 2011; Qin et al. 2011; Fang and Liu 2008; Bao et al. 2012, 2013; Tai et al. 2013)

Scheme 5.3
scheme 3

Anti-amyloidogenic properties of compound FLZ, a squamoside analogue of a constituent from Annona glabrais

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5.2.5 Ginseng

The available types of ginseng, all belonging to the Araliaceae family, are Asian ginseng (Panax ginseng), American ginseng (P. quinquefolus) and Siberian ginseng (Eleutherococcus senticosus). Water extracts of the dried roots and leaves of Panax ginseng have been used as a stimulant/tonic, diuretic and digestive aid in traditional Chinese medicine for over 2,000 years. Ginseng phytomedicines are sold as ergogenic supplements to enhance mental and physical performance – reflective of Chinese medicine where body and mind are inseparable – to provide resistance to stress, and to prevent ‘exhaustion’ and disease. The major active principles of P. ginseng extracts are ginsenosides, which are glycosylated derivatives of the triterpene dammarane such as for instance Rg1. Rg3 is one of the major constituents of ginseng. The ginsenosides that reduce Aβ levels in animal models and other in vitro studies are summarized in Table 5.2.

Table 5.2 The anti-AD bioactivities of P. ginseng constituents
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The diverse constituents and multiple actions of ginseng constituents in the CNS reviewed recently (Kim et al. 2013a) will not be elaborated here. The in silco analysis of 12 ginsenosides (see Table 5.2) revealed those with potential interactions with the BACE1 receptor active site essential for enzyme inhibition (Karpagam et al. 2013). Further studies included ADMET screening to find the drug-like ginsenosides with a specific ability to cross blood brain barrier (BBB), and to determine safety/toxicity. Also the BACE1-ginsenosides complexes were further subjected to a molecular dynamics simulation to study their stability and hydrogen bond interactions. Of the 12 ginsenosides, CK, F1, Rh1, and Rh2 were predicted to pass the BBB and ADMET analysis predicted toxic effects for ginsenosides Ro and ginsenoside Rg1, while Rf showed low oral absorption in human gastrointestinal tract. These results suggest that of the seven ginsenosides demonstrating BACE1 inhibition, only the four monoglucosylated ginsenosides CK, Rh1, Rh2, and F1 pass the BBB and possess satisfactory drug-like properties. BACE1 and ginseng inhibitor complex crystal structural data to describe their binding modes would provide an accurate picture of the number and length of hydrophobic and hydrogen bond ginsenoside-enzyme interactions. These two descriptors have reliably predicted the activity of synthetic BACE1 inhibitors (Nastase and Boyd 2012). The wider implications of this research are that the brain-permeation/bioactivity of di- and multi-glycosylated ginsenosides is questionable. Intestinal microbial metabolism (Zhang et al. 2013d) similar to that of Rb1 shown in Fig. 5.2 may be a pre-requisite for their neuroprotective activity.

Fig. 5.2
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The structures of ginsenosides Rb1 and its metabolic transformation product K, and those of Rh1, Rh2, F1

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5.2.6 Herbal Foods, Formulations and Supplements

L-3-n-Butylphthalide (Fig. 5.3) was first extracted from Chinese celery (Apium graveolens var. secalinum). The chemically prepared compound is used as an anti-hypertensive herbal medicine for the treatment of ischemic stroke, and has therapeutic application for the prevention of vascular dementia by up-regulation of Akt expression in the hippocampus (Huai et al. 2013; Peng et al. 2008, 2012). Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB), a precursor to n-butylphthalide, has neuroprotective effects on cerebral ischemic, vascular dementia and Aβ-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation. Further research has suggested that dl-PHPB could be an attractive multi-target neuronal protective agent for the treatment of AD (Zhao et al. 2013; Peng et al. 2014). Z-ligustilide found in R. angelica sinensis promotes the activities of superoxide dismutase and thereby reduces oxidative stress in brain tissues; protects against Aβ-induced neurotoxicity and is a potential therapeutic against vascular dementia (Huang et al. 2008; Kuang et al. 2006; Feng et al. 2012; Xin et al. 2013). An appreciation of the amount of Z-ligustilide, the bioactive component in 10 g of herb is detailed in Fig. 5.3. The pharmacokinetics and bioavailability of Z-ligustilide were determined by the systematic investigation in Sprague–Dawley rats. With an extraction efficiency of 62.3 %, 0.93 g Z-ligustilide was isolated from 100 g of R. angelica sinensis. Therefore, based on animal pharmacokinetic data, with the absolute bioavailability at a 50 mg/kg dose of 75.44 %, a single medicinal use of 10 g of the herb may deliver 43.7 mg of Z-ligustilide.

Fig. 5.3
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Herbal bioactive compounds and Z-ligustilide bioavailability calculations (Zhang et al. 2014)

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Studies on 27 herbs revealed that some lesser known herbs such as Curcuma aromatica and Zingiber officinale (ginger) extracts effectively protected cells from Aβ insult, followed by Ginkgo biloba (ginkgo), Polygonatum sp., Cinnamum cassia (Chinese cinnamon), Rheum coreanum (Korean rhubarb), Gastrodia elata (gastrodia), and Scutellaria baicalensis (skullcap) (Kim et al. 2007). With regards to herbs, spices and food products that disrupt, destabilize or reverse amyloid aggregation, these have been investigated for their ability: (i) to detour the generation of toxic amyloid precursors (off-pathway); (ii) to prevent the assembly of amyloid oligomers into fibrils; (iii) to inhibit fibril growth and deposition; (iv) to disassemble preformed fibrils; and (v) to promote Aβ clearance. The structures of the active anti-dementia constituents in Chinese herbs most widely used and investigated as potential amyloid inhibitors are presented in Fig. 5.4.

Fig. 5.4
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Structures of the major chemical families of active constituents found in Chinese herbs having anti-dementia and β-amyloid anti-aggregation activities

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Many herbs are considered to be responsible for multiple beneficial effects such as improving vascular dementia, energy homeostasis, improving mitochondrial antioxidant capacity, and anti-inflammatory neuroprotection. The many and varied constituents in herbs can also enhance the bioavailability and bio-effectiveness of the active constituents and thus have more therapeutic value than individual compounds. Preliminary animal model studies suggest that antioxidants in spearmint and rosemary might be useful in modulating age-associated cognitive decline. Furthermore, rosemary improves local blood circulation, relieves pain, has anticancer activity, and controls blood lipid and anti lipid peroxidation. Carnosic acid, one of the major phenolic constituents of rosemary, is a pro-electrophile specifically activated by the oxidative stress pathological state resulting in its conversion from the hydroquinone to the oxidized quinone form, before it activates the Keap1/Nrf2 pathway leading to gene induction of the antioxidant response element (ARE) and gene products that protect against oxidative stress. A survey of Chinese herbs and herbal formulas that improve cognition in dementia rated the following as the top 10 herbs for improving memory: Poria cocos, Radix et rhizome ginseng, Radix polygalae, Radix et rhizome glycyrrhizae, Radix Angelica sinensis, Rhizoma acori tatarinowii, Semen ziziphi spinosae, Radix rehmanniae, Radix ophiopogonis and Rhizoma zingiberis (Lin et al. 2012; Shen and Chen 2013). The anti-Aβ bioactivity and neuroprotective mechanisms of many of these herbs are outlined in Table 5.3. In Schemes 5.4 and 5.5, the focus is on the particular herbs and spices that can effectively protect against amyloid disease. Their Aβ disaggregation properties and inhibition of tau protein hyperphosphorylation are highlighted (Yoshida et al. 2014; Xian et al. 2012; Fujiwara et al. 2006; Frydman-Marom et al. 2011; Kumaraswamy et al. 2013; Airoldi et al. 2013; Zeng et al. 2013).

Table 5.3 The top Chinese herbs for improving memory, their major constituents, anti-dementia and neuroprotective actions
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Scheme 5.4
scheme 4

Anti β-amyloid effects of food spices and herbs

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Scheme 5.5
scheme 5

Chinese herbs most commonly used against dementia and AD

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5.2.7 Chinese Herbal Formulae for Anti-dementia Protection

Baicalin, jasminoidin, and cholic acid structures (Fig. 5.5) are the main active components of Qingkailing (QKL, Scheme 5.6). QKL is one of the most well-known Chinese herbs and is an aqueous preparation containing extracts of 7 herbs (Cheng et al. 2012). Baicalin is a strong antioxidant; jasminoidin elicits a protective effect on neurons under a broad range of stresses and cholic acid strongly promotes the expression of growth factors in the brain. Upon further investigation of the therapeutic effects and molecular mechanisms of a combination of the three components baicalin, jasminoidin and cholic acid (CBJC) in a rat dementia model, it was found that they significantly up-regulated genes in the forebrain related to neurogenesis and antioxidant neuroprotection (Zhang et al. 2013a).

Fig. 5.5
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Neuroprotective constituents of Chinese herbal formulae against dementia

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Scheme 5.6
scheme 6

Herbal combinations and formulations used for dementia treatment

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Kai-xin-san (KXS), a Chinese herbal decoction contains Ginseng Radix rhizoma, R. Polygalae radix, R. Acori Tatarinowii, and Poria. KXS has been used in China to treat stress-related psychiatric diseases with the symptoms of depression and forgetfulness. A chemically-standardized water extract of KXS applied to astrocytes significantly stimulated the expression and secretion of neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in a dose-dependent manner: the stimulation was both in mRNA and protein expression (Zhu et al. 2013; Man et al. 2012). Rhizoma Acori Tatarinowii (grassleaf or sweet-flag rhizome), the rhizome of Acorus tatarinowii Schott, is used in TCM as an anti-convulsant; it can prevent convulsions as well as convulsion-related GABAergic neuron damage in the brain (Liao et al. 2005).

From the analysis of 1,232 traditional Chinese medicine formulae for anti-dementia (Kong et al. 2009) it was suggested that the most commonly used herbal formulation (Fig. 5.5) was Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Radix Polygalae Tenuifoliae and Rhizoma Acori Tatarinowii. Their major chemical constituents and anti-AD activities are summarized in Table 5.4.

Table 5.4 Neuroprotective effects of the four herb TCM formulae commonly used for dementia treatment
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Yukukansan (Yigan San) is a classical TCM formula used for dementia (Iwasaki et al. 2005b) composed of seven herbs, Angelica acutiloba, Atractylodes lancea, Bupleurum falcatum, Poria cocos, Cnidium officinale, Uncaria rhynchophylla and Glycyrrhiza uralensis, in a ratio of 3:4:2:4:3:3:1.5. Clinical randomized controlled trials (RCTs) revealed that Yigan San improved behavioral and psychological symptoms of dementia that include aggression, agitation, screaming, wandering, hallucinations and delusions. Yigan San reduces cholinesterase inhibitor-resistant visual hallucinations in dementia patients (Iwasaki et al. 2005a). Yigan San improved psychiatric symptoms and sleep structure in dementia patients (Shinno et al. 2008). The mechanisms of action are related to regulating multiple signal pathways, such as the glutamatergic neurotransmitter system, the serotonin receptor and excitotoxicity (Ho et al. 2011).

A key challenge in validating and translating fundamental science of herbal medicines into better anti-dementia outcomes is to evaluate and scrutinize clinical trial outcomes using scientific research methodologies. Some animal and clinical research performed on herbs leading to improved cognitive health providing options for dementia management and prevention is presented in Table 5.5.

Table 5.5 Clinical trials with herbs to counteract dementia and AD
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5.3 Summary and Future Outlook

The individual-based interventionist approach against dementia and AD for extending healthy life — better diet and regular exercise — is effective, however it needs much greater promotion, acceptance and adoption early on in life. Alkaloids, monoterpenes, diterpenes, triterpenes, flavonoids, and polyphenolic compounds represent the most prevalent classes of herbal constituents with anti-AD bioactivity. It is unclear to what extent many of these bioactive phytochemicals utilized in single or herbal formulae doses can reach the brain in sufficient concentrations, and in a biologically active form, to exert their beneficial neuroprotective effects. The majority of herbs are consumed as aqueous extracts so their formulation has to provide increased bioavailability and BBB permeability (Hugel and Jackson 2014). An overview of the metabolism and strategies for enhancing polyphenol bioavailability (Lewandowska et al. 2013) include encapsulation of phospholipid-polyphenol complexes; formation of inclusion complexes with cyclodextrins or dendrimers; use of bioactive analogues; derivatisation (e.g., amidation); use of adjuvants (e.g. piperine) as absorption enhancers; and transdermal delivery systems.

It is imperative that herbs and herbal constituents are consumed regularly and in sufficient quantities in the diet. Indeed, for in vivo and clinical studies, producing active compounds and extracts in large quantities is an important challenge for the utilization of natural products as therapeutic agents. Generally speaking, herbal products offer a wide range of brain-targets, nutritional benefits, safe dosage, long-term applications and efficacious treatment of AD pathology. The focus on engagement of sustainable optimal biochemical performance through diet and factors influencing it, including lifestyle choices, are key to a better mental health.