Introduction

Alzheimer's disease (AD) is a progressive inexorable loss of cognitive function associated with the presence of senile plaques in the hippocampal area of the brain. The disease is the most common form of dementing illness among middle-aged and older adults, affecting more than 5 million Americans, a number estimated to increase to 7.7 million by 2030. Symptoms typically appear after age 60, and some early-onset forms of the disease are linked to a specific genetic defect. Although the etiology is unknown, genetic factors clearly play a role in 10% to 15% of cases [1]. So far, e orts to find a cure for AD have been disappointing, and the drugs currently available to treat the disease address only its symptoms and with limited effectiveness. The underlying pathogenesis is a loss of neurons in the hippocampus, cortex, and subcortical structures [2]. Early disease shows a loss of short-term memory, inability to learn new information, mood swings, difficulty in finding words, forgetting names, and losing items. Frustration, hostility, and irritability are common emotional features exhibited by patients with AD. In severe cases, patients become totally incontinent, memory is completely lost, and sense of time and place disappears. Patients become totally dependent upon others and eventually require comprehensive care. Owing to the patient's total dependency upon others, placement in a nursing home with full-time nursing care becomes necessary. Thus, AD presents a considerable problem in patient management as well. It is believed that therapeutic intervention that could postpone the onset or progression of AD would dramatically reduce the number of cases in the next 50 years [1].

Herbal medicine offers several options to modify the progress and symptoms of AD. There has been a new trend in the preparation and marketing of drugs based on medicinal plants, and their scientific and commercial significance appears to be gathering momentum in health-relevant areas. These plant-derived products are carefully standardized, and their efficacy and safety for a specific application have been demonstrated [3–7].

Ayurvedic medicine is a system of traditional medicine native to India, and Ayurvedic practitioners have developed a number of medicinal preparations and surgical procedures for the treatment of various ailments. An entire body of literature in the Ayurvedic texts deals with the nervous system and disorders associated with it. Nervous system disorders, called 'VataVyadhi' in Sanskrit, were thought to be brought on by imbalances of Vata, the biological air humor, the energy that moves through the brain and the nerves (the ancients considered nerve impulses to be a kind of wind or air traveling through the body) controlling both voluntary and involuntary functions. Hence, Vata derangements always involve some weakness, disturbance, or hypersensitivity of the nervous system. Included in these texts are direct references to age-associated memory loss, preventive care, and therapeutic interventions. These texts explain the use of several herbs and their qualities and energetics for nervous system disorders, including memory loss typically seen in older adults, but only recently have there been mechanistic studies on the role of these herbs in nervous system disorders and dementias, including dementia associated with AD [8]. Indeed, several scientific studies have described the use of various Ayurvedic medicinal plants termed 'nervines' and their constituents to strengthen the functional activity of the nervous system and restoration of memory [8, 9]. Phytochemical studies have shown the presence of many valuable compounds, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects [5–8, 10].

The present review puts together research on various Ayurvedic medicinal plants that have shown promise in reversing the AD pathology. The report summarizes information concerning the phytochemical, biological, and cellular activities and clinical applications of these various plants in order to provide sufficient baseline information that could be used in drug discovery campaigns and development processes, thereby providing new functional leads for AD. Below we describe the various Ayurvedic medicinal nervine herbs that are recommended for AD and their actions on the brain.

Ashwagandha (Withania somnifera)

Ashwagandha is used extensively in Ayurveda as a nervine tonic, aphrodisiac, and 'adaptogen' and helps the body adapt to stress [9, 11]. Ashwagandha is a member of the nightshade (Solanaceae) family, and the root is the part that is widely used. It is categorized as a rasayana (rejuvenative) and is believed to possess antioxidant activity, free radical scavenging activity, and an ability to support a healthy immune system [12]. Unlike other adaptogens, which tend to be stimulating, Ashwagandha has a calming effect and thus may be particularly indicated in people with AD [13]. A total alkaloid extract of Ashwagandha root exhibited a calming effect on the central nervous system (CNS) in several mammalian species, suggesting the use of this herb to produce relaxation. A recent double-blind, randomized, placebo-controlled study of the effects of Ashwagandha on stress found that it reduced symptoms of stress and inability to concentrate and reversed forgetfulness in a dose-dependent manner, and 500 mg/day was more effective [14]. No additional adverse effects were found.

Ashwagandha contains steroidal compounds of great interest to researchers, such as the ergostane-type steroidal lactones, including withanolides A to Y, dehydrowithanolide R, withasomniferin A, withasomidienone, withasomniferols A to C, withaferin A, and withanone. Other constituents include the phytosterols sitoindosides VII to × and beta-sitosterol as well as alkaloids (for example, ashwagandhine, cuscohygrine, tropine, pseudotropine, isopelletierine, and anaferine), a variety of amino acids (including tryptophan), and high amounts of iron [9, 15]. A subset of these components (withanamides) has been shown to scavenge free radicals generated during the initiation and progression of AD. Neuronal cell death triggered by amyloid plaques was also blocked by withanamides [13, 16–18]. Molecular modeling studies showed that withanamides A and C uniquely bind to the active motif of beta-amyloid (Aβ 25-35) and prevent fibril formation [17, 19]. In the CNS, Ashwagandha has been reported to increase memory and learning [20]. Aqueous extracts of this herb have been found to increase cholinergic activity, including increases in the acetylcholine content and cholineacetyl transferase activity in rats and this might partly explain the cognition-enhancing and memory-improving effects [21, 22]. In addition, recent reports have provided exciting information on the ability of this herb to stimulate neurite outgrowth [23]. Treatment with the methanol extract of Ashwagandha caused neurite outgrowth in a dose- and time-dependent manner in human neuroblastoma cells [21, 24]. The levels of two dendritic markers, MAP2 and PSD-95, were found to be markedly increased in cells treated with Ashwagandha, suggesting that it stimulates dendrite formation [21, 24]. In an extension of the above study, the same research group treated cultured rat cortical neurons with amyloid peptide that induced axonal and dendritic atrophy and loss of pre- and postsynaptic stimuli. Subsequent treatment with a methanol extract of Ashwagandha induced significant regeneration of both axons and dendrites. In addition to the reconstruction of pre- and postsynapses in the neurons, methanol extracts of Ashwagandha reversed amyloid peptide-induced memory deficit in mice [24]. These in vivo effects of Ashwagandha were maintained even after the discontinuance of the drug administration. Similarly, preliminary studies from this laboratory revealed significant neurogenesis in the dentate gyrus region only in J20 mice - mice that express the mutant form of human amyloid precursor protein (APP) bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutations - that were fed a diet containing the whole herb (Ashwagandha root powder, 2.5 g/kg body weight) in comparison with J20 mice that received only normal chow (unpublished data). Although the data mentioned above are quite promising for the use of Ashwagandha as an anti-AD agent, additional clinical trials need to be conducted to support its therapeutic use. While the herb has been used successfully in Ayurvedic medicine for centuries, a systematic study of the acute or chronic toxicity of this herb or its various components is still lacking and additional studies are warranted to confirm the therapeutic significance of this herb [9].

Note added in proof

While the manuscript of this review was in the review process, Sehgal et al. (Proc Natl Acad Sci U S A 2012, 109: 3510-3515) reported that oral administration of a semipurified extract of the Ashwagandha (W. somnifera) root reversed behavioral deficits, plaque load, and accumulation of beta-amyloid peptides in mouse models of AD. This therapeutic effect of W. somnifera was mediated through upregulation of liver low-density lipoprotein (LDL) receptor-related protein (LRP).

Turmeric (Curcuma longa)

Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. Derived from the rhizome and root, turmeric is used as a spice and coloring agent and in traditional medicine in Asia. The active constituents are thought to be turmerone oil and water-soluble curcuminoids, including curcumin [25]. Curcumin is the principal curcuminoid and is responsible for the yellow color of the turmeric root [25–27]. Turmeric is anti-inflammatory, antiseptic, and antibacterial and has long been used in the Indian system of medicine to treat a variety of conditions. This versatile spice helps detoxify the liver, balance cholesterol levels, fight allergies, stimulate digestion, and boost immunity [28]. Epidemiologic studies show a 4.4-fold lower incidence of AD in Southeast Asian countries where turmeric is commonly used as a dietary spice [29]. Other studies indicate that the non-steroidal anti-inflammatory property of turmeric is associated with a reduced risk of AD [30]. Indeed, when fed to aged mice with advanced plaque deposits similar to those of AD, curcumin reduced the amount of plaque deposition [27, 31–33]. It reduced oxidative damage and reversed the amyloid pathology in an AD transgenic mouse [32, 33]. Direct injection of curcumin into the brains of the mice with AD not only hampered further development of plaque but also reduced the plaque levels [33]. AD symptoms characterized by inflammation and oxidation were also eased by curcumin's powerful antioxidant and anti-inflammatory properties [33]. In addition, a low dose of turmeric (160 parts per million, or ppm) reduced proinflammatory cytokine levels that are linked to the neuroinflammatory cascades involved in neuritic plaque pathogenesis [32]. Curcumin's in vitro ability to inhibit lipid peroxidation and neutralize reactive oxygen species may be several times more potent than that of vitamin E [34]. Toxicity studies were conducted by the National Cancer Institute by administering turmeric oleoresin (organic extract of turmeric) in feed to groups of male and female rats and mice for 13 weeks and 2 years. There were no acute or chronic clinical findings related to toxicity in either rats or mice receiving 2,000, 10,000, or 50,000 ppm of turmeric oleoresin [35].

Owing to the promising findings in animal models, clinical trials of oral curcumin supplementation in patients with early AD are already under way [10, 36]. In addition, the results of a six-month randomized, placebo-controlled, double-blind, clinical trial of curcumin in 27 patients with AD found that oral supplementation with up to 4 g/day of curcumin was safe [37]. Larger controlled trials are needed to determine whether oral curcumin supplementation is efficacious in AD [38].

Brahmi (Bacopa monnieri)

Brahmi (also known as Bacopa) is a bitter-tasting creeper plant found in damp and marshy areas and is commonly used in Ayurvedic medicine as a nerve tonic, diuretic, and cardiotonic and as a therapeutic agent against epilepsy, insomnia, asthma, and rheumatism [7, 39]. The principal constituents of Bacopa monnieri (BM) are saponins and triterpenoid bacosaponins that include bacopasides III to V, bacosides A and B, and bacosaponins A, B, and C. Other saponin glycosides include the jujubogenin bisdesmosides bacopasaponins D, E, and F. Other constituents include alkaloids, plant sterols, betulic acid, polyphenols, and sulfhydryl compounds that confer antioxidant activity [7, 39, 40]. Thus, BM could act by reducing divalent metals, scavenging reactive oxygen species, decreasing the formation of lipid peroxides, and inhibiting lipoxygenase activity [41]. Traditionally, BM was used to improve memory and cognitive function [42]. The BM extracts have been investigated extensively for their neuropharmacological effects and their nootropic actions [39, 42–44]. In the hippocampus, BM enhances protein kinase activity that may contribute to its nootropic action [45]. BM also inhibited cholinergic degeneration and displayed a cognition-enhancing effect in a rat model of AD [46]. A team of researchers also reported that a standardized extract of BM reversed the cognitive deficits induced by intracerebroventricularly administered colchicines and ibotenic acid into the nucleus basalis magnocellularis [47]. In the same study, BM also reversed the (a) depletion of acetylcholine, (b) reduction in choline acetyltransferase activity, and (c) decrease in muscarinic cholinergic receptor binding in the frontal cortex and hippocampus [47]. BM extracts protected neurons from beta-amyloid-induced cell death by suppressing cellular acetylcholinesterase activity. In addition, BM extract-treated neurons expressed a lower level of reactive oxygen species, suggesting that Brahmi restrained intracellular oxidative stress [48].

An enriched phytochemical composition of BM was evaluated for short-term safety and tolerance in healthy adult volunteers. A detailed examination of clinical, hematological, biochemical, and electrocardiographic parameters did not reveal any untoward effects in any of the volunteers who received oral administration of a single capsule containing the enriched herb for 30 days (300 mg for the first 15 days and 450 mg for the next 15 days) [49]. On the basis of the above-mentioned study and other clinical studies carried out to establish the efficacy of BM in memory and attention disorders, BM has now been introduced in the Indian market for treatment of memory and attention deficit disorders [50–53]. These clinical studies with Bacopa serve as a model for the way forward for other herbs to ascertain their effective dosage range, the time required to attain therapeutic levels, and their effects over a longer term of administration.

Shankhpushpi (Convolvulus pluricaulis)

Various species for Shankapushpi, including Convolvulus pluricaulis (CP), Convolvulus microphyllus, Evolvulus alsinoides, and Clitoria ternatea (CT), have been described. Shankhpushpi is a common plant in India, where the whole plant is used in various formulae as a nervine tonic for improvement of memory and cognitive function [18, 54, 55]. A wide range of secondary metabolites, including triterpenoids, flavonol glycosides, anthocyanins, and steroids, has been isolated and may be responsible for Shankhpushpi's nootropic and memory-enhancing properties in addition to other pharmacological activities [55–58]. It is believed that Shankhpushpi calms the nerves by regulating the body's production of the stress hormones, adrenaline, and cortisol [58]. It is also recommended for nervous disorders such as stress, anxiety, mental fatigue, and insomnia [7, 43, 55]. The ethanolic extract of CP and its ethyl acetate and aqueous fractions significantly improved learning and memory in rats [59]. The ethanolic extract of CP also possesses significant antioxidant activity when tested in vitro [18, 54, 59, 60]. An ethanolic extract of the whole plant, when administered to cholesterol-fed gerbils, reduced serum cholesterol, LDL cholesterol, triglycerides, and phospholipids significantly [55]. A dose-dependent enhancement of memory was observed in mice that were administered extracts of CP. Similarly, administration of CP extracts for 7 days enhanced memory in aged mice. Hippocampal regions associated with the learning and memory functions showed a dose-dependent increase in acetylcholine esterase activity in the CA1 and CA3 area with CP treatment [61]. Specifically, administration of aqueous root extract of CT to neonatal rat pups resulted in improved retention and spatial learning performance, indicating the memory-enhancing property of CT. In addition, a significant increase in acetylcholine content was observed in the hippocampi of CT-treated rats in comparison with age-matched controls. Increase in acetylcholine content in the hippocampus may be the neurochemical basis for their improved learning and memory [62–64]. Young adult rats intubated with aqueous root extract of CT showed a significant increase in passive avoidance learning and retention. A significant increase in dendritic intersections, branching points, and dendritic processes arising from the soma of neurons in the amygdale region in CT-treated rats was observed in comparison with age-matched saline controls, suggesting that CT enhances memory by increasing the functional growth of neurons [65].

Gotu kola (Centella asiatica)

In the Ayurvedic system of medicine, gotu kola is one of the important rejuvenating herbs for nerve and brain cells and is believed to be capable of increasing intelligence, longevity, and memory [44, 66]. Asiaticoside derivatives, including asiatic acid and asiaticoside, were shown to reduce hydrogen peroxide-induced cell death, decrease free radical concentrations, and inhibit beta-amyloid cell death in vitro, suggesting a possible role for gotu kola in the treatment and prevention of AD and beta-amyloid toxicity [67]. Gotu kola extracts reversed the beta-amyloid pathology in the brains of PSAPP (APP/Sw × PS1M146L) mice and modulated the components of the oxidative stress response [66–70].

Jyotishmati (Celastrus paniculatus)

Jyotishmati is a treasured medicinal herb that is revered for its effects on the brain and has been used for centuries in Ayurveda for sharpening the memory and improving concentration and cognitive function [71]. Aqueous extracts of CP seeds have cognition-enhancing properties and antioxidant properties. CP extracts protected neuronal cells against H2O2-induced toxicity in part by virtue of their antioxidant properties and their ability to induce antioxidant enzymes. CP extracts also protected neuronal cells against glutamate-induced toxicity by modulating glutamate receptor function. In addition, the CP extracts protected neuronal cells by virtue of their free radical scavenging properties, reducing lipid peroxidation, and also by their ability to induce the antioxidant enzyme catalase [68, 72–75]. In addition, aqueous extracts of CP seed have dose-dependent cholinergic activity, thereby improving memory performance [68].

Jatamansi (Nardostachys jatamansi)

Similar to its Western relative valerian, Jatamamsi is safe and balancing in its effects. The plant has a rich history of medicinal use and is highly regarded in the Ayurvedic system of medicine. The rhizomes and roots of the plant have medicinal value and, therefore, have been the focus of chemical studies. They contain a variety of sesquiterpenes and coumarins. The sedative sesquiterpene valeranone, which is also found in valerian, is a major component of the root essential oil. Other terpenoids include spirojatamol, nardostachysin, jatamols A and B, and calarenol. Jatamansi is the predominant coumarin [76–78].

Studies on its role in the CNS revealed that extracts of Nardostachys jatamansi (NJ) alleviated all of the symptoms of chronic fatigue syndrome (CFS) in rats. CFS triggered increases in lipid peroxidation, nitrite, and superoxide dismutase levels, and low catalase levels were all reversed by NJ extracts. The data indicate the powerful antioxidant property of NJ [79]. Similarly, an alcoholic extract of this plant administered to both young and aged mice significantly improved learning and memory and also reversed the amnesia induced by diazepam and scopolamine. Furthermore, it reversed aging-induced amnesia due to the natural aging of mice, suggesting that the compounds in this plant may prove to be useful in restoring memory in older individuals as well as in patients with age-associated dementia [80].

Guggulu

Guggulu is an oleogum resin exuding from the cracks and fissures in the bark or from incisions from several different plant species, including Commiphora mukul, C. molmol, C. abyssinica, C. Burseraceae, and C. whighitii. The oleogum resin of guggulu is a mixture of 30% to 60% water-soluble gum, 20% to 40% alcohol-soluble resins, and about 8% volatile oils. Water-soluble constituents include mucilage, sugars, and proteins. Alcohol-soluble constituents include the commiphoric acids, commiphorinic acid, and the heerabomyrrhols. Among the volatile constituents are terpenes, sesquiterpenoids, cuminic aldehyde, eugenol, and the ketone steroids Z-and E-guggulsterone, and guggulsterols I, II, and III [81–83]. Guggulu also contains ferulic acids, phenols, and other non-phenolic aromatic acids that are potent scavengers of superoxide radicals and could potentially be of importance for the treatment of AD and other oxidative stress-related disease [84–86]. The gum resin has been used for thousands of years in the treatment of arthritis, inflammation, obesity, and disorders of lipid metabolism.

In animal models and in humans, administration of guggulipid is reported to significantly lower both serum LDL cholesterol and triglyceride levels [87–89]. Insight into the mechanism of action for the hypolipidemic activity was provided by the demonstration that guggulu is an effective antagonist of the bile acid receptor farnesoid × receptor [87, 90]. Epidemiologic and biochemical data suggest a link between cholesterol, APP processing, and AD [91–96]. These studies indicate that there is a decreased prevalence of AD associated with the use of cholesterol-lowering drugs [93–96]. Decreased neuronal cholesterol levels, in turn, inhibit the beta-amyloid-forming amyloidogenic pathway, possibly by removing APP from cholesterol and sphingolipid-enriched membrane microdomains. These intriguing relationships raise the hopes that cholesterol-lowering strategies may influence the progression of AD [91–96]. A recent study demonstrated that gugulipid has a significant protective effect against the streptozotocin-induced memory deficit model of dementia; the effect can be attributed to its cholesterol-lowering, antioxidant, and anti-acetylcholine esterase activity. These observations suggest gugulipid as a potential anti-dementia drug [88].

Administration of Ayurvedic herbs

The biggest challenge to drug delivery into the CNS is bypassing the blood-brain barrier (BBB) as it limits access to the CNS. For decades, the BBB has prevented the use of many therapeutic agents for treating brain-related diseases and injuries, including AD, stroke, brain tumor, head injury, and other CNS disorders. Ayurveda relies on some novel methods of administering herbs or their preparations (or both) to treat CNS disorders. However, proper studies are lacking to demonstrate whether these herbs or their components given orally or by some other means cross the BBB and reach the CNS. One novel method of herbal delivery, called 'NASYA', involves intranasal delivery of dry herbal powders or medicated oils and is a practical, non-invasive, rapid, and simple method to deliver the therapeutic agents into the CNS. The use of medicated oils, which require that the herbs be cooked in four parts oil and 16 parts water over a low flame until all of the water evaporates, ensures the transport of lipophilic and lipid-soluble molecules across the BBB membrane, where hydrophilic compounds demonstrate minimal permeation [97]. Intranasal administration offers numerous benefits for drug delivery into the CNS, and interest in this non-invasive route of administration has increased. The delivery is rapid, bypasses the BBB, and directly targets the CNS, thereby reducing systemic exposure and side effects [98–102].

A second, simple method of administration involves application of the medicated oil on the body and massaging the areas with gentle or deep hand strokes. It is not clear whether this technique facilitates the transport and movement of the herbal components through the BBB. Indirect evidence from recent studies points to such an exciting possibility. Significant brain functional activation changes together with increased cerebral blood flow were observed in participants who received a massage. Massage reduced the levels of stress-related serum cortisol, arginine vasopressin, and salivary stress protein chromogranin A with concomitant increases in circulating lymphocytes and regional cerebral blood flow [103–106]. It is tempting to speculate that, in addition to the above-mentioned hormonal changes, application of medicated oil followed by a gentle massage could relax the tight junctions between endothelial cells in the CNS vessels and facilitate the entry of solutes and other components into the CNS.

Ayurveda also relies on several transcranial oleation therapies for nervous system disorders that are non-systemic and non-invasive. Procedures like Shirodhara (gentle dripping of the medicated oil on the forehead), Shirobasti (a special leather cap is placed over the shaved head of a patient and medicated oil is poured and retained over the head for 30 to 45 minutes), ShiroAbhyanga (medicated oil is smeared on the head followed by a gentle massage), and ShiroSeka (medicated oil is poured over the head in a continuous stream) may also influence hormonal and cerebral blood flow levels to a degree similar to that of Ayurvedic massage as mentioned above [107–110]. While scientific studies regarding the permeation of the herbal components into the CNS through transcranial oleation therapies are lacking, recent work again points to the possibility that the endothelial cells facilitate the entry of the solutes through the frontal lobe and prefrontal cortex [109, 110].

Aromatherapy, another popular method in the Ayurvedic system, involves the use of volatile plant materials known as essential oils for healing purposes for altering a person's mood and cognitive function. The essential oils are incorporated through steam inhalation or are topically applied to the face and arms. Aromatherapy used with massage may help to calm agitated people with dementia. There is some preliminary evidence that aromatherapy using various essential oils may have some potential for improving cognitive function, especially in patients with AD [111–113].

Conclusions

The pharmaceutical industry is facing serious challenges as the drug discovery process for neurodegenerative diseases is becoming extremely expensive, riskier, and critically inefficient. A significant shift from a single-target to a multi-target drug approach, especially for chronic and complex disease syndromes, is being witnessed. Approaches based on reverse pharmacology (from the clinic to the bedside) also offer efficient development platforms for herbal formulations. The Ayurvedic system of medicine has garnered increasing recognition in recent years with regard to diet and treatment options. Early development of Ayurvedic herbal supplements required only anecdotal or epidemiologic information (or both) without an understanding of the mode of action. The Ayurvedic medicine industry has come a long way from when it was considered unnecessary to test Ayurvedic formulations prior to use, to several randomized, double-blind, controlled studies and to the introduction of good manufacturing practice guidelines for the industry. It has taken a more rigorous scientific and quality-enhanced approach to provide 'proof of concept' and a 'mode of action'. It might be worth pointing out that, while Ayurvedic therapeutics has been prescribed for centuries for neurodegenerative diseases (including dementias), only recently have there been Western, mechanistic studies on AD; however, these mechanistic studies point to the same mechanisms addressed by the Ayurvedic therapeutics (for example, increase in nerve growth factors and neurotrophic factors and reduction in inflammation and oxidative damage), providing strong support for herbal therapy for AD [11]. It is hoped that the strong knowledge base of Ayurveda coupled with combinatorial sciences and high-throughput screening techniques will improve the ease with which Ayurvedic products and formulations can be used in drug discovery campaigns and development process, thereby providing new functional leads for AD and other age-associated neurodegenerative diseases.