Nootropic Medicinal Plants: Therapeutic Alternatives for Alzheimer’s disease

Accepted Manuscript Title: Nootropic Medicinal Plants: Therapeutic Alternatives for Alzheimer’s disease Authors: Swati Vyas, S.L. Kothari, Sumita Kachhwaha PII: DOI: Article Number:

S2210-8033(19)30038-7 https://doi.org/10.1016/j.hermed.2019.100291 100291

Reference:

HERMED 100291

To appear in: Received date: Revised date: Accepted date:

7 October 2016 2 February 2019 8 July 2019

Please cite this article as: Vyas S, Kothari SL, Kachhwaha S, Nootropic Medicinal Plants: Therapeutic Alternatives for Alzheimer’s disease, Journal of Herbal Medicine (2019), https://doi.org/10.1016/j.hermed.2019.100291 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Nootropic Medicinal Plants: Therapeutic Alternatives for Alzheimer’s disease Swati Vyas1, S.L.Kothari1,2 and Sumita Kachhwaha1* 2Institute

of Botany, University of Rajasthan, Jaipur, Rajasthan, India–302004 of Biotechnology, Amity University, Rajasthan, Jaipur, Rajasthan, India-302019

First author Given Name - Swati Family Name – Vyas Affiliation - Department of Botany, University of Rajasthan, Jaipur, Rajasthan, India–302004 Email – [email protected]

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Second author Given Name – S. L. Family Name – Kothari Affiliation - Institute of Biotechnology, Amity University, Rajasthan, Jaipur, Rajasthan, India-302019 Email – [email protected]

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1Department

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Corresponding author Given Name - Sumita Family Name – Kachhwaha Affiliation - Department of Botany, University of Rajasthan, Jaipur, Rajasthan, India–302004

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Graphical abstract:

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Email - [email protected]

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Highlights  Alzheimer’s disease and other dementias have become huge global concern and burden over the years.  Current FDA-approved drugs are few and symptomatic in nature. They are often associated with adverse effects.  Nootropic medicinal plants have shown potential as promising source of alternative medicines for treating Alzheimer’s disease  This review explains detailed methodology as well as presents the alarming statistics of AD, currently prescribed drugs along with their limitations, therapeutic targets and synergetic strategies for AD drug development and gaps in AD research  This review enlists some of the most important plants as leads against Alzheimer’s disease and their therapeutic properties

Abstract: With the rise in the ageing population in the last few decades, dementia has emerged

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as a serious global health issue. Alzheimer's disease (AD) is the most common type of

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dementia. Despite extensive drug development research, only a limited number of FDA-

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approved drugs are available for AD. As these drugs provide symptomatic relief only and are frequently associated with adverse effects, there remains an urgent need for developing

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alternative approaches to AD therapeutics. Several medicinal plants are reported as nootropics that improve mental and cognitive functions via influencing different physiological pathways

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of the brain. In this regard, ethnopharmacological screening of medicinal plants is considered one of the major approaches. This review presents the alarming statistics of AD, currently prescribed drugs along with their limitations, therapeutic targets and synergetic strategies for

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AD drug development. Many studies have confirmed the employment of medicinal plants and their ethnopharmacological suitability as an alternative approach for research and development

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of AD therapeutics which are highlighted in this review. Moreover, this article addresses the importance of standardization and metabolite profiling of medicinal plants in the field of pharmacognosy. Also, the checkpoints of taking translational drug development from the level

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of laboratory research up to patient treatment are precisely mentioned.

Keywords: Alzheimer’s disease, Neuropharmacognosy, Medicinal plants, Nootropics, Ethnopharmacology, Secondary metabolites

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Contents: 1. Introduction 2. Methodology 3. Alzheimer’s disease: a call for global attention

5. Checkpoints in pharmacognosy of Botanical medicines 6. Measurements to combat these challenges

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7. Secondary metabolites: chief contributors 8. Pharmacologically important plants for AD 9. Conclusion Conflict of interest

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Acknowledgements

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4. Ethnopharmacology: nootropics as alternative lead for AD therapeutics

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References

1. Introduction

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Alzheimer's disease is an irreversible progressive neurodegenerative disorder characterized by gradual deterioration of memory, cognition, speech, language, visual-spatial

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perception, behavior and daily function activities eventually leading to complete dementia and death. Extracellular senile neuritic plaques (NP) and intracellular neurofibrillary tangles (NFT) are hallmarks of AD (Blennow et al., 2006; Blennow et al., 2015; Chiba, 2013; Corbett et al.,

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2013; Ji et al., 2014; Rafii and Aisen, 2009; Rosén et al., 2015) which are observed in brain parenchyma and/or in brain vessels (Poulin and Zakzanis, 2002). Disruption of synaptic and neuronal function, reduction in dendritic arborization, reduction in neurotransmitter levels

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occurs, leading to progressive loss of neurons and brain volume (Stadelmann et al., 1999; Yankner, 1996). Fig. 1 compares these features of a healthy brain with brain of AD patient at

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severe stage.

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Fig. 1: Schematic diagram comparing a normal healthy brain and brain at severe stage of Alzheimer’s disease. AD brain shows decrease in brain volume, accumulation of NP (red coloured fibrous accumulations) and NFT (green colored accumulations), loss of synaptic connections, neuronal loss.

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The NP are aggregations (10–160 µm in diameter) of beta-amyloid (Aβ) protein covered by

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dead neurons, microglia, astrocytes, apolipoprotein E, α-1-antichymotrypsin, and proteoglycans (D'Andrea, 2014; Mott and Hulette, 2005; Perry et al., 2013). Aβ is formed via

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sequential processing of amyloid precursor protein (APP), by three endoproteases: α-, β- and γ-secretase (Skovronsky et al., 2001), which cut APP at several positions to produce Aβ peptides of different lengths (23, 40, 42, 56 amino acids) (Chow et al., 2010; De Strooper and Annaert, 2000; Kawasumi et al., 2002). It is now known that the major isoforms of Aβ in the plaques are Aβ4-42, Aβ1-

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42, and Aβ1-40 (Portelius et al., 2010). According to the amyloid cascade hypothesis it is suggested that Alzheimer’s disease is initiated by certain mutations in the APP, PSI, and PSII genes which

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lead to preferential APP cleavage forming a longer version of the Aβ peptide. These Aβ peptides have tendency to form β-sheets which further accumulate to form neuritic senile plaques around neurons in brain tissue, eventually leading to synaptic injury and dendritic loss.

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As Alzheimer’s disease progresses, neuronal degeneration and death occur, leading to dementia and other symptoms of the disease (Blennow et al., 2015; Hardy, 2009; Hardy and Allsop, 1991; Hardy and Higgins, 1992). Intraneuronal NFTs are primarily composed of tau protein arranged in hyperphosphorylated paired helical strands (Hardy and Allsop, 1991; Imbimbo et al., 2005; Pastorino and Lu, 2006). Hyperphosphorylated tau self-aggregates, forming intermediate

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aggregates, paired helical filament and NFTs (Iqbal et al., 2013; Lee et al., 2005; Spires-Jones et al., 2009) . The hyperphosphorylation of tau disrupts its normal function in regulating vesicle-axonal transport due to destabilizing of the neuronal cytoskeleton which leads to the reduction of dendritic spines and accumulation of neurofibrillary tangles along with toxic species of soluble tau (Gooch and Stennett, 1996; Iqbal et al., 1998) causing inflammation, oxidative cytotoxicity and neurodegeneration. Oxidative stress induced by reactive oxygen species is prominent in AD. Oxidative

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stress leading to free radical attack on neural cells plays a role in neuro-degeneration. Although

oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species

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(ROS) generation contribute to a range of disorders such as Alzheimer’s disease, Parkinson’s

disease, aging and many other neural disorders. The histopathological and the experimental evidence that support the impact of oxidations on the pathogenesis of AD (oxidative-stresshypothesis) is constantly increasing (Behl and Moosmann, 2002; Christen, 2000; Di Giovanni

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et al., 2008; Markesbery, 1999; Smith et al., 2000; Steele et al., 2007; Varadarajan et al., 2000).

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With the progression of AD one of the important changes observed in the brain of AD

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patients is a decrease in hippocampal and cortical levels of the neurotransmitter acetylcholine (ACh). On the behavioural side, the important decrease of ACh levels causes impairment in

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cognitive function (Cummings, 2004; Selkoe, 1996). Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine

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in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission.

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Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins (Čolović et al., 2013). Apolipoprotein E (ApoE) plays a crucial role in Aβ clearance. Mutation in Apo-E4

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might occur in the pathogenesis of AD either by a toxic gain-of-function, loss of neuroprotective function, or both (Liu et al., 2013). ApoE is present in NP (neuritic plaques)

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and NFT (neurofibrillary tangles) (Franczak and Maganti, 2004; Raber, 2008). Mitochondrial dysfunction has been found in the brains of both AD patients and AD transgenic mouse models, as well as in cell-lines expressing mutant APP or treated with Aβ (Dragicevic et al., 2011; Eckert et al., 2008; Reddy et al., 2012). The N-methyl-D-aspartate (NMDA) receptor is very important for controlling synaptic plasticity and memory function. In Alzheimer’s disease, however, excess glutamate can be

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released from damaged cells, leading to chronic overexposure to calcium, which can speed up cell damage (Furukawa et al., 2005; Li and Tsien, 2009; Lleo et al., 2006; Olivares et al., 2012). Mitochondrial dysfunction, oxidative stress, and decreased metabolism may be a common pathway to several neurodegenerative conditions, including normal aging of brain (Jordan et al., 2003; Paradis et al., 2003). System biology suggests that effective treatment of complex diseases – like AD and cancer – needs to restore disrupted disease networks, which often requires simultaneous (or even dynamically simultaneous) modulation of multiple

pathways may lead to effective and worthwhile therapeutic solutions to AD.

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proteins (targets)/pathways (Azmi, 2013; Mei et al., 2016). Therefore, targeting multiple

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AD is progressive in nature which means it manifests gradually and worsens with

passing time (Jack et al., 2009; Reiman et al., 2012; Villemagne et al., 2013) before symptoms appear (Fig. 2). Depending on tentative brain changes and respective clinical changes the stages

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of AD progression have been defined (Delacourte et al., 1999; Delrieu et al., 2011; Rafii and Aisen, 2015; Selkoe, 2011; Singh et al., 2011). The brain changes of AD may begin 20 or more

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years before symptoms appear (Jack et al., 2009; Reiman et al., 2012; Villemagne et al., 2013). The time

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between the initial brain changes of AD and the symptoms of advanced AD is considered by scientists to

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represent the “continuum” of AD. At the start of the continuum, the individual is able to function normally despite these brain changes. Further along the continuum, the brain can no longer compensate for the

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neuronal damage that has occurred, and the individual shows subtle decline in cognitive function. Later, the damage to and death of neurons is so significant that the individual shows obvious cognitive decline, including symptoms such as memory loss or confusion as to time or place. Later still, basic bodily functions such as swallowing are impaired leading to consequent death (Alzheimer'sAssociation, 2014;

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Rafii and Aisen, 2015).

Fig. 2: Flowchart summarizing progressive stages and continuum of Alzheimer’s disease

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(Alzheimer'sAssociation, 2014; Rafii and Aisen, 2015)

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A limited number of routinely used FDA-approved drugs have made treating AD a challenging task. Moreover, these drugs symptomatically treat AD providing a temporary relief rather than curing the disease by modifying its pathology and have frequently been associated with adverse drug effects. Consequently, there is an urgent requirement for developing alternative AD therapeutics. Plant-based remedies for treating health conditions have recently received enormous interest although they have been used by mankind since antiquity. This time-honored

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utilization of medicinal plants has established a valuable database with anecdotal evidence

suggesting safety and efficacy of numerous species. Medicinal plants offer an inexhaustible

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array of compounds as a result of secondary metabolism causing high chemical diversity over

other natural sources. Even the currently used drugs are either semi-synthetically or directly derived from plants (Table 1). Investigators have shown great interest in exploration of traditionally used medicinal plants, their derivatives and even their combinations for AD drug

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research (Butler, 2004).

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Table 1: Some examples of currently used drugs derived from plants frequently cited in

Therapeutic target

Reference(s)

Artemisia annua

Artemisinin

Malarial Treatment

(Woerdenbag et al., 1990)

Atropa belladonna

Atropine

Tiotropium

Chronic Obstructive Pulmonary Disease

(Hansel and Barnes, 2002)

Leptospermo ne

Nitisinone

Antityrosinaemia

(Das, 2017)

Coffea sp.

Caffeine

Caffeine citrate

Cognitive enhancer, CNS stimulant, psychoactive

(Estler, 1982; Pluskal and Weng, 2018)

Cannabis sativa

Dronabinol and Cannabidiol

Natural product

Pain Relievers

(Abuhasira et al., 2018; Nielsen et al., 2018)

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Active Phytocompo und(s)

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Callistemon citrinus

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Compounds derived from active phytocompound Arteether, Endoperoxide Sesquiterpene Lactone

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Medicinal Plant

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the literature

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Capsaicin

Natural Product

Galanthus nivalis

Galantamine

Natural product

Papaver somniferum

Morphine

Apomorphine hydrochloride

Nicotiana tabacum

Nicotine

Natural product

Pain Relievers; Alzheimer’s Disease Alzheimer’s Disease

(Jiang et al., 2013; Sharma et al., 2013) (Graul, 2004; Scott and Goa, 2000) (Deleu et al., 2011)

Severe pain, Parkinson's Disease para(Jasinska et al., sympathomimetic 2014) stimulant, performanceenhancing effects on cognition, alertness, and focus

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Capsicum annuum

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2. Methodology

A critically exhaustive literature survey related to research on Alzheimer’s disease and

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medicinal plants along with their nootropic uses was carried out up to March 2017. Peer-

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reviewed research papers, review articles and book chapters published in Springer, Elsevier,

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Nature, BMC, PLOS One, Oxford University Press, John Wiley & Sons and Wiley Online Library served as primary sources of data collection for this review article. Also, several online

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(NCBI, Science Direct, Scopus, webpages and conference proceedings, Traditional Chinese Medicine Database@Taiwan, Medicines Quality Database and Indian Medicinal Plant Database) and offline (conference proceedings, thesis and books) resources were used. Bioinformatics Infrastructure Facility Center sponsored by DBT, New Delhi located at

articles.

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University of Rajasthan campus facilitated access of subscription required closed access

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Google scholar and PubMed were employed for literature searching using the following keywords:

Alzheimer’s disease, medicinal plants, herbal medicine, traditional medicine systems,

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nootropic plants and their properties, metabolic profiling of medicinal plants, standardization of medicinal plants, herbal market and its statistics and neuropharmacognosy. Several articles have already been published on AD and the phyto-therapeutic approach towards it but this review provides comprehensive information regarding the alarming statistics of AD, currently prescribed drugs along with their limitations, therapeutic targets and synergetic strategies for AD drug development, nootropics as alternative lead for AD

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therapeutics, challenges in developing new phytopharmaceuticals and measures to combat them along with a list of pharmacologically important plants for AD. The review thus addresses some of the gaps present in the current AD literature and its neuropharmacognosy research. 3. Alzheimer’s disease: a call for global attention AD is the most common cause of dementia followed by vascular dementia, Lewy

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body’s dementia and Parkinson’s disease and may contribute to 60–70% of dementia related

cases. Dementia is a syndrome characterized by acquired impairment of higher mental

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functioning in the presence of normal consciousness, including impairment of memory and

other functional domains (Alzheimer’sAssociation, 2015; Hilton and Shivane, 2015) interfering with social or occupational functioning leading to impeded daily routine activities of the patients (Franczak and Maganti, 2004; Huey et al., 2015; Qaseem et al., 2008). It is one

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of the major causes of disability and dependency among older people worldwide and is forming

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an increasing and considerable burden on patients, caregivers, and society (Devi and Ohno,

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2012). The onset and progression of AD appears to be influenced by complex interactions between genetic and environmental risk factors and Heritable mutations in the genes like APP,

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PSEN1 and PSEN2, APOE4 (Karch et al., 2012).

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Alarming AD statistics

With the increase in demographic ageing, the AD global burden has considerably increased. There are almost 900 million people aged 60 years and over, living worldwide, who

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are most vulnerable to AD. Rising life expectancy is contributing to rapid increases in numbers, and is associated with increased prevalence of chronic diseases like dementia. In 2015, 47 million people worldwide were estimated to be living with dementia. This number is expected

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to double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050. The global costs of dementia have increased from US$ 604 billion in 2010 to US$ 818 billion in 2015, an

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increase of 35.4 %. Current estimate of US$ 818 billion represents 1.09 % of global GDP (Alzheimer’sAssociation, 2015; Dastmalchi et al., 2007; Malik et al., 2011; Wimo et al., 2013). Estimated number of dementia cases in India were 3.7 million in the year 2010. Also, the total societal costs estimated was about 14,700 crore Indian Rupees. While the numbers are expected to double by 2030, costs would increase three times (Shaji et al., 2010). The total financial burden levied comprises of direct, indirect and intangible costs. Direct financial burden covers day care at home, medications, nurse and physician visits, 10

hospitalization and medical tests. Indirect financial burden is ascribed estimated cost of resources lost due to the illness which includes unproductivity of the patient, death of the patient, hampered productivity of the caregiver and unpaid caregiving time. Intangible costs are those related to pain and suffering endured by patients and families, and deterioration of patient and caregiver quality of life. Medical treatment may have economic benefits by slowing the rate of cognitive decline, delaying institutionalization, reducing caregiver hours, and improving quality of life. Pharmacologically economic evaluations have shown positive results

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regarding the effect of drug therapy on nursing home placement, cognition, and caregiver time (Zhu and Sano, 2006).

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Routinely used Drugs

Currently, a few FDA-approved drugs (Table 2) are available and that too only provide symptomatic and temporary relief. Moreover, they have frequently been associated with adverse drug effects (Birks et al., 2009; Feldman et al., 2003; Heinrich and Teoh, 2004; Lee et

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al., 2015; Petersen et al., 2005; Rhee et al., 2001; Rösler et al., 1999; Sramek et al., 2000). One

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such example is Tacrine. It’s usage led to many side effects like nausea, vomiting, salivation,

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sweating, bradycardia, hypotension, collapse, convulsions and fatal hepatotoxicity. Hence, it was withdrawn from the US market in 2012 (Mutahir et al., 2016).

Drug

Adverse effects

Pfizer U.S. Pharmaceuticals Group / Eisai Co., Ltd.

Selective AChE inhibitor

Diarrhoea, nausea, anorexia, vomiting, muscle cramps, fatigue in some cases

Novartis International AG

Non-selective inhibitor Nausea, vomiting and diarrhoea of cholinesterases

Galantamine (Reminyl®; Reminyl ER)

Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Specifically inhibits AChE

Nausea, vomiting, anorexia, weight loss acutely at higher doses

*Tacrine (Cognex®)

Pfizer U.S. Pharmaceuticals Group

Non-selective cholinesterase inhibitor

Hepatotoxicity and gastrointestinal symptoms such as nausea, anorexia, diarrhea

Memantine

Forest Laboratories, Inc.

Non-competitive inhibitor of NMDA receptors

Mild and not common, constipation, confusion, headache, dizziness, tiredness

(Aricept®)

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Rivastigmine

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Mechanism

Donepezil

Manufacturer

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Table 2: FDA-approved medications for treatment of AD

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(Exelon®)

(Namenda®; Namenda XR®)

* Withdrawn from the US market in 2012 (Mutahir et al., 2016).

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Therapeutic Targets for AD AD is a complex condition and its underlying mechanisms remain unanswered. However, this complexity has provided a number of therapeutic targets and strategies (Piau et al., 2011) such as acetylcholine esterase (AChE), N-methyl-d-aspartate (NMDA) receptor, glycogen synthase kinase 3β (GSK3β), cyclin-dependent kinase 5 (CDK5) and β-secretase. These are summarized in the form of a flowchart (Fig. 3). Various trends for uncovering the novel and efficient agents for AD has been outlined by several workers, which mainly aims at

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the development of disease modifying drugs targeting the pathogenic mechanism of AD (Salomone et al., 2012); researching for novel biotargets, seeking multi-targeting drugs acting

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simultaneously on a group of principal biotargets in the disease pathogenesis (Geldenhuys and Van der Schyf, 2013) and re-evaluation of the already known drugs for neurologic diseases

treatment (Corbett et al., 2013). Some of the therapeutic strategies for AD followed by many workers involve inhibition of acetylcholinesterase, protease and secretase; promoting anti-

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aggregation of mutant Aβ, aiding defibrillation and disaggregation of Aβ fibrils and plaques,

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boosting clearance of Aβ; modulation of kinase, inhibiting tau hyperphosphorylation,

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employing tau β-sheet breakers, inhibiting glycogen-synthase kinase 3; combating oxidative damage as well as mitochondrial dysfunction, supplementing natural antioxidant products;

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devising anti-inflammatory drugs; achieving optimal ion concentrations through modulation of ion channels; overcoming mutant ApoE and APP; reduction of synaptic and dendritic loss

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along with repairing axonal transport, confronting neuronal loss, engaging neuro-regenerative compounds (Butler, 2004; Chen et al., 2016; Hua and He, 2016; Jia et al., 2014; Kudo, 2016;

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Mathew et al., 2012; Newman and Cragg, 2012; Rishton, 2008; Williams et al., 2011).

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therapeutic interventions (red colour) (Williams et al., 2011)

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Fig. 3 Schematic flow chart summarizing the pathways of Alzheimer’s disease and their proposed

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ApoE = Apolipoprotein E; AChE = Acetylcholine esterase; PKC = Protein kinase C; GSK-3 = Glycogen synthase kinase-3; cdk-5 = cyclin-dependent kinase 5; APP = Amyloid Precursor Protein; sAPP = soluble

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APP; Aβ = β-amyloid peptide; p3 = fragment generated by cleavage of APP by α- and γ-secretase; AICD = APP Intra-Cellular Domain short peptides; C99 = C-terminal fragment of 99 kDa.

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α and β indicate processing by, respectively, α and β secretases.

4. Ethnopharmacology: nootropics as alternative leads for AD therapeutics Ethnopharmacology is often defined as the interdisciplinary scientific exploration of

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biologically active agents traditionally employed or observed by man. Its objectives are to rescue and document an important cultural heritage besides evaluation of the agents employed

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(Holmstedt and Bruhn, 1983). Reviews establish that ethnopharmacological screening is one of the main approaches used in drug discovery (Adams et al., 2007; Clement et al., 2004; Houghton and Howes, 2005; Houghton and Seth, 2003; Howes and Houghton, 2003; Kumar,

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2006; Natarajan et al., 2013; Zhang, 2004). There is an established correlation between the ethnomedicinal uses of plants and the current use of their derived drugs (Adams et al., 2007; Jones et al., 2006; Natarajan et al., 2013). This approach aims to preserve the use of plants described in the literature that have not been investigated in pharmacological and phytochemical studies. Therefore, bibliographical surveys may represent the first step of a scientific research process (Denise Otsuka et al., 2010). This appears to be a particularly

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rewarding approach because it has been reported that of 122 drugs derived from medicinal plants which are in use worldwide, 80% can be traced back to their ethnomedicinal uses (Jones et al., 2006). The herbs acting on the brain are known as nootropic herbs (Gk. Nootropic = acting on the mind) and their isolated constituents referred to as smart drugs (Rathee et al., 2008; Russo and Borrelli, 2005). These smart drugs can be drugs, supplements, nutraceuticals, and functional foods that improve mental functions (Dwivedi et al., 2012) possibly by modifying

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neurochemical production (neurotransmitters, enzymes, and hormones), by enhancing the brain’s oxygen supply, by ameliorating synaptic plasticity and transmission or by rejuvenating

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neuronal growth (Ingole et al., 2008). They tend to balance the nervous system, restoring a sense of well-being and relaxation eventually leading to optimum health and self-healing (Wichtl, 2004).

The alternative systems of medicine include Ayurveda, Siddha, Homeopathy, Unani

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and Traditional Chinese Medicine that all have roots in natural products (Eisenberg et al., 1993;

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Howes et al., 2017). The use of natural products is limited not only to herbs but marine, animal

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and mineral preparations that have been purified by the traditional healers for medicinal use (Malhotra et al., 2001). Alternative medicine is becoming popular and an increasing number

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of patients are visiting alternative medicine healers (Kidd, 1999; Singh, 2003). The term complementary and alternative medicine is customary in describing various alternative

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approaches to augment the health of mind, body and spirit in order to enhance traditional medical approach to disease treatment. There is an increase of worldwide use of traditional medicines due to many influences that include a rise in the cost of health care, information

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technology and a greater global conscience toward the importance of holistic medicine. In countries such as Japan, Korea, India and China, botanical therapeutics are often administered by a practicing medical professional and are classified as traditional `medicines'. In the USA,

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many of these same plants are termed `supplements' which are sold with applicable legal restriction preventing sale and dispensation without a claim to `treat' a disease (Mazzio and

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Soliman, 2009).

Ayurveda encompasses philosophy, science and religion and is a very complex system

of knowledge applied to daily life. Rasayana tantra – geriatrics including rejuvenation therapy – is one of eight major disciplines in Ayurveda. Charaka Samhita defined rasayana as a treatment to attain longevity, intelligence, freedom from age related disorders, youthful appearance, optimum strength of physique and sense organs, maintain language ability and improve memory (Bala and Manyam, 1999; Manyam, 1999). Rasayana is not merely a drug 14

therapy but a regimen covering the general mode of life, social conduct, behavior, diet and the use of specific restorative remedies (Adams et al., 2007). The ayurvedic materia medica contains a number of formulations of medicinal plants reputed to improve memory and intellect. Cognitive functions are well recognized in Ayurveda and Sanskrit whereby terms existed such as Buddhi for intelligence and Chittanasa (Chitta means mind, nasa means loss of) for dementia (Mantle et al., 2000; Manyam, 1999). Ayurveda provides a list of plants known for their nootropic activity. ‘Reverse

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pharmacology’ is the basis of Ayurveda-based drug discovery, in which depending upon the wide scale use by the population, the drug candidates are identified and subsequently validated

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in clinical trials (Kaur et al., 2017). Phytodrugs are relatively less toxic and are bioavailable to

exert multiple synergistic effects, including improved cognitive and cholinergic functions This results in significant reduction in the cost and time consumed in the overall procedure of drug discovery (Kumar, 2006; Padma, 2005).

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About 65-80% of the world’s population living in developing countries depends

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essentially on plants for primary health care. Herbal medicines play a crucial role in the world

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health and serve as source for approximately 25% of all modern medicines such as aspirin, artemisinin, ephedrine, and paclitaxel (Cragg and Newman, 2001; De Smet, 1997; Farnsworth,

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1966; Zhang et al., 2015) and represents a substantial proportion of the global drug market (WHO, 1998). Factors such as rising health concerns, growth of key demographics, and

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increasing consumer desire to lead a healthy life and to avoid dependence on synthetic drugs are the major drivers contributing to the enormous growth of this market (Dubey et al., 2004; Ho and Tan, 2011; Pal and Shukla, 2003).

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The herbal market represents a substantial proportion of the global drug market (WHO, 1998). Total global herbal market is of the size of US$ 62.5 billion in 1997, growing at a rate of 10% -15% per annum and is projected to reach US$ 115 billion by 2020 (Bacchetta and

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Beverelli, 2012; David et al., 2015; De Silva, 1997; Gupta, 2003; Hamilton, 2004; Mishra et al., 2016; Raskin et al., 2002; WHO, 2002, 2005, 2007).

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Several reviews have supported the clinical effects of a number of commonly used

herbal medicines regarding the treatment of AD (Anekonda and Reddy, 2005; Saini et al., 2012; Santos-Neto et al., 2006). System biology suggests that effective treatment of complex diseases like AD and cancer needs to restore disrupted disease networks, which often requires simultaneous (or even dynamically simultaneous) modulation of multiple proteins (targets)/pathways (Azmi, 2013). Herbal ingredients are thought to work synergistically to contribute to the therapeutic effect of each individual ingredient. 15

Pharmaceutical researchers often use bibliographic surveys to search for sources of new drugs (Ten Kate and Laird, 1999). The application of new bioinformatics database systems about herbal texts holds great promise for identifying novel bioactive compounds for pharmacotherapy (Buenz et al., 2004). Some International Databases, such as Dr. Duke's Phytochemical and Ethnobotanical Databases (Duke and Beckstrom-Sternberg, 1994), provide information about pharmacological activities, ethnopharmacological data, chemical compounds and data from tests on animals and humans for thousands of species from all over

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the world. The World Health Organization defines psychoactive substances as those that, when

taken in or administered into the system affect mental processes (Denise Otsuka et al., 2010).

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Thus, psychoactive plants are those ingested in a simple form or as a complex preparation to

affect the mind or alter the state of consciousness (Rätsch, 2005). It is possible to classify psychoactive drugs as: depressors, which decrease the activity of the central nervous system, such as alcohol, hypnotics and anxiolytics; stimulants, which increase this activity, such as

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amphetamines and cocaine; and those which disrupt this activity, such as hallucinogens and

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anticholinergics (Chaloult, 1971). Ethnopharmacological surveys of psychoactive substances

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(Rodrigues and Carlini, 2004; Schultes, 1993; Schultes and Reis, 1995) are important tools, as they may indicate potential bioactive substances for researchers engaged in the development

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of medicines for psychiatry. Databases with information on the ethnopharmacological uses of psychoactive plants and their chemical compounds support research groups that focus on these

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plants as potential therapeutics. Using bioinformatics tools and meta-analysis, phytochemicals can be screened in silico for their efficacy, safety, mechanism of action. This can also provide

EP

lead for synthesis of analogues with customized characters.

5. Checkpoints in pharmacognosy of botanical medicines Pharmacognosy relates to the study of naturally derived potential drug substances and

CC

analysis of their various properties for further phytopharmaceutical development. There are numerous challenges obstructing the path of botanical research such as quality, specific

A

composition, safety, efficacy, optimal dosage, mode of action, batch-to-batch variations, storage, mass manufacturing and distribution of botanical preparations. Dealing with plants regarding drug development is highly sensitive affair as every minute detail majorly affects the resultant product and its properties. This can cause manufacturing of poor-quality products leading to ambiguous, incorrect or non-reproducible results. Ambiguity in the identification of plant material may harm the whole process. The plant part collected, time and geographical

16

location of collection as well as drying method, extraction procedures and storage details also affects the properties of botanical preparations. Chemical characterization and biological profiling botanical preparations yields necessary information. Chemical composition of plants is majorly influenced by genetic and environmental factors. This tends to affect the batch-tobatch uniformity of botanical preparations due to its chemical complexity. However, reasonable chemical consistency with appropriate specifications within acceptable range of variation leading to establishment of minimum quality is targeted. This can be difficult to

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achieve since some compounds occur in plants in only trace amounts but exert important biological impacts. Determination of mode of action of botanical preparation and the role

SC R

played by its individual constituents is often hindered due to the fact that pharmacological

effects cannot directly be compared with the effects of single compounds. There is an evident synergism of compounds present in the botanical preparations. Moreover, some compounds show different or changed characteristics when isolated. Since there are major concerns with

U

globalization of botanical preparations as discussed above, “fit-to-purpose” standardization

Measurements to ensure the quality of botanical medicines

Collection of plant material

M

6.

A

N

approach might be helpful (Cooper and Kronenberg, 2009).

Correct identification of the desired plant or its part, is the foremost checkpoint to

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ensure the quality of botanicals medicines. Therefore, acquisition of an authentic voucher specimen along with detailed documentation regarding plant’s Latin name, the plant part collected, time and geographical location of collection for reference must be carried out.

EP

Voucher specimen can be referred to at any stage for questions regarding identity and chemical composition of the plant material used. Uniform drying, processing and proper storage of dried plant material should be followed. There must be a thorough check for infections and pests.

CC

Standardization of Medicinal Plants The extraction method and solvent used strongly influence the chemical composition

A

of the resultant extract and subsequently its biological activity. Enumeration and characterization of the chemical constituents of the botanical preparation serves as a fingerprint for its identity and biological activities. Qualitative coupled with quantitative analysis of primary and secondary metabolites has been reported by several investigators. Any part of the plant such as seeds, leaves, bark, roots, flowers, stigma, stem, fruits and pods might contain important metabolites (Cragg and Newman, 2001). Primary metabolites (carbohydrates, amino acids, proteins, nucleic acid and lipids) are the building blocks, precursor to metabolic 17

pathways and pharmacologically active principles of the plants. They are found ubiquitously throughout the plant kingdom (Tatsuta and Hosokawa, 2006). Some of the plants also produce a diverse array of secondary metabolites that confer special properties to those plants. Secondary metabolites are frequently accumulated by plants in smaller quantities than the primary metabolites (Karuppusamy, 2009). Preliminary standardization using colorimetric analysis, florescence analysis of plant powder in ordinary and ultra-violet light after treatment with different chemical reagents and extractive values has been demonstrated by numerous

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studies (Agrawal and Pal, 2013; Dastmalchi et al., 2007; Ekka and Dixit, 2007; Gopalkrishnan

and Ringmichon, 2016; Kalaivanan et al., 2016; Khosa and Prasad, 1971; Laloo et al., 2012;

SC R

Maurya, 2016; Mehra, 2016; Nayar et al., 1978; Padhar et al., 2016; Sholapur and Patil, 2013). Metabolite Profiling: Documenting the metabolites

Metabolic fingerprinting in medicinally important plants is critical for establishing the identity and quality as well as for resolving the metabolic pathways of herbal medicines

U

(Aiyegoro and Okoh, 2010; AOAC, 2005; Awoyinka et al., 2007; Ayoola et al., 2008; Chhabra

N

et al., 1984; Farnsworth, 1966; Kaur and Arora, 2009; Kubmarawa et al., 2007; Kunle et al.,

A

2012; Maurya, 2016; Odebiyi and Sofowora, 1977; Tiwari et al., 2011; Tona et al., 1998; Wani, 2007). Spectroscopic together with analytical systems such as IR, NMR and GC-MS have been

M

used in many studies for metabolite profiling (Jain et al., 2012; Nakabayashi et al., 2009; Thooptianrat et al., 2017). These tools have been successfully applied to the characterization

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of various herbs and plant extracts for quality control, authentication, determining geographical origin, and detecting adulteration of herbal drugs and extracts (Defernez and Colquhoun, 2003). The metabolite profiling of a plant facilitates an understanding of complex biochemical

EP

processes within a plant. Analytical systems such as IR, NMR and GC-MS have provided significant advancement for the rapid identification of wide range of phytochemicals. These have opened new avenues for plant metabolomics research such as pharmacological

CC

investigations, functional genomics, comprehensive chemical analysis, metabolite-to-gene

A

network studies (Jain et al., 2012; Nakabayashi et al., 2009).

Crude Extracts over Isolated Compounds Instead of using the crude whole plant, researchers together with the pharmaceutical companies are racing to identify, isolate, extract and synthesize the active principle components of medicinal plants. Multiple reports and even clinical trials however have encountered toxic effects of isolated and/or synthesized active compounds (Burgos‐ Morón et al., 2010; DanceBarnes et al., 2009; Jiao et al., 2009; Meyer et al., 1982; Rates, 2001). Isolated compounds 18

show different or changed properties such as solubility, ability to cross blood brain barrier, efficacy and dosing. This could be explained by the fact that besides the active ingredients, plants contain other substances such as minerals, vitamins, volatile oils, glycosides, alkaloids and bioflavonoids which work together to confer the particular medicinal properties to any herbal plant due to their chemical partnership (Khemani et al., 2012; Li et al., 2016; Maity et al., 2009).

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7. Secondary Metabolites: The Chief Contributors

The use of plants in the treatment of diseases is attributed to their secondary

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compounds. An enormous variety of secondary metabolites such as phytosterols, flavonoids, alkaloids, terpenes, saponines, quinones and polyphenols are synthesized exclusively by plants for various purposes such as a chemical defense against herbivores and microbial attack (Wink et al., 2005), toxicant and repellent for insects, attractants for pollinators, protection against

U

photo-damage (Chew et al., 2009b). Along with playing a major role in adaptation of plants to

N

their environment, these molecules also represent an important source of active

A

pharmaceuticals. Plant constituents may be isolated and used directly as therapeutic agents or as starting materials for drug synthesis or they may serve as models for pharmacologically

M

active compounds in drug synthesis. The general research methods includes proper selection of medicinal plants, preparation of crude extracts, biological screening, detailed chemo

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pharmacological investigations, toxicological and clinical studies, standardization and use of active moiety as the lead molecule for drug design (Wink et al., 2005). Secondary metabolites are usually classified based on their biosynthetic pathways.

EP

They include alkaloids, terpenoids, sterols, flavonoids, phenolics, saponins, resins, oleoresins, lactones and volatile oils (Gershenzon, 2002; Harborne, 1999; Skovronsky et al., 2001). A diversity of secondary metabolites is produced by plants and phenolic compounds

CC

are one of its most important groups. Phenolics possessing at least one aromatic ring (C6) bearing one or more hydroxyl groups posses’ ideal structural chemistry to scavenge free

A

radicals. In general, phenolic compounds act as potential metal chelators as well as inhibit lipid per-oxidation by quenching free radicals via formation of resonance-stabilized phenoxyl radicals. Flavonoids are probably the most important class of natural phenolics and have the ability to donate electrons or hydrogen atoms readily, so they can directly scavenge reactive oxygen species (Michalak, 2006). Flavonoids and phenolic acids are shown to have potential health benefits whereby one of their biological focuses on the relationship between their antioxidant activity, as hydrogen donating free radical scavengers, and their chemical structures 19

(Croft, 1998; Rice-Evans et al., 1996). With an increase in new technologies, certain animal models and studies with cell line in culture show observed activities may be due to superoxide and hydrogen peroxide produced during the auto-oxidation of polyphenols (Apak et al., 2013; Chen et al., 2016; Chew et al., 2009a; Tabart et al., 2009). Plant polyphenolics such as flavonoids and tannins possess free radical-scavenging properties because of their favorable structural chemistry. In general, phenolic compounds act as potential metal chelators as well as inhibit lipid per-oxidation by quenching free radicals via forming resonance-stabilized

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phenoxyl radicals. Among the multifarious phenolic compounds, flavonoids are probably the most important class (Hertog et al., 1993; Middleton et al., 2000). Alkaloids are derived from

SC R

amino acids produced by a large variety of organisms including bacteria, fungi, plants, and animals. They often have pharmacological effects and are used as medications, as recreational

drugs, or in entheogenic rituals. They are used as analgesics (codeine), nerve stimulants (strychnine), local anesthetic (cocaine), antihypertensive (reserpine), cardiac depressants

U

(quinine) or antileukemic (vincristine) (Manske and Holmes, 2014; Pelletier, 1999; Shi et al.,

N

2014). Phytosterols are present in wide range of flowering plants and gymnosperms. The

A

common phytosterols reported from plants are β-sitosterol, stigmasterol and campesterol. Plant sterols which exhibit structural similarities to cholesterol are known to reduce LDL-cholesterol

M

levels in humans by interfering with cholesterol intestinal absorption (Burg et al., 2013; Singh

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et al., 2013).

8. Pharmacologically important plants for AD A broad range of medicinal plants have recently been reported for their nootropic

EP

effects. AChE inhibitors, neuroprotective agents, antioxidants as well as compounds acting on mutant proteins have been reported by various investigators. The production of phytochemicals by plants affecting such complex brain functions as neuroregeneration, memory, cognition or

CC

mood could presumably be explained by the biosynthesis of these chemicals to deter predators or attract pollinators or disseminators by targeting the nervous system.

A

The in vitro dual anti-cholinesterase and β-secretase activities of Camellia sinensis L.

extract (tea) were investigated and reported that tea infusions contain biologically active principles, perhaps acting synergistically, that may be used to retard the progression of AD (Okello et al., 2004). Plants used in Thai traditional rejuvenating and neurotonic remedies were investigated using Ellman’s colorimetric method in 96-welled microplates for their acetylcholinesterase inhibitory activity. It was noticed that methanolic extracts from roots of Stephania suberosa and Tabernaemontana divaricata exhibited 90% inhibitory activity 20

(Ingkaninan et al., 2003). Bacopa monnieri ethanolic extract competitively inhibited AChE in different regions of rat brain (Aguiar and Borowski, 2013; Ahirwar et al., 2012). Bacopa monnieri is a reputed nootropic plant reviewed by many researchers (Russo and Borrelli, 2005; Saini et al., 2012). A review comprehensively surveyed the available literature of plants that had been tested for AChE inhibitory activity and reported numerous phytoconstituents such as (alkaloids and glycosides), promising plant species and their methanolic extracts as AChE inhibitors (Mukherjee et al., 2007). Flavonoids extracted from the ethyl acetate extract of the

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whole plants of Argimonia pilosa, during screening for AChE inhibitors from 180 medicinal plants exhibited highly significant AChE inhibition (Jung and Park, 2007). A total of 26 wild-

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grown Lamiaceae species from Croatia were evaluated for their AChE inhibitory, antioxidant

and phytochemical properties. Results showed that the extracts of Mentha piperita, M. longifolia, Salvia officinalis, Satureja montana, Teucrium arduini, T. chamaedrys, T. montanum, T. polium and Thymus vulgaris possessed strong inhibitory activity against AChE

U

at 1 mg/mL concentration. These findings indicated Lamiaceae species to be a rich source of

N

various natural AChE inhibitors and antioxidants useful in the prevention and treatment of

A

Alzheimer’s and other related diseases. (Vladimir-Knežević et al., 2014).

M

Similar studies were previously conducted on the methanol, ethyl acetate and chloroform extracts of 48 selected Croatian plants out of which the methanolic extract of Salix

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alba L. cortex showed 50.8% AChE inhibition and all other extracts showed high antioxidative property (Jukic et al., 2012). Aqueous and methanolic extracts of 11 Danish folk medicinal plants traditionally used for improvement of memory and cognition were found to exhibit significant AChE inhibitory activity in a dose-dependent manner for 5 plants extracts; namely,

EP

Corydalis cava, Corydalis intermedia, Corydalis solida ssp. laxa and Corydalis solida ssp., Slivenensis (Adsersen et al., 2006). Recently, infusions and decoctions of leaves from various

CC

plants were tested which concluded that rosmarinic acid, scutellarein 4′-methyl ether 7-Oglucuronide and (16S)-coleon E were the main compounds responsible for the high acetylcholinesterase inhibition activity (31% inhibition with 0.5 mg of extract/ml) and

A

antioxidant activity (IC50 = 45.8 ± 0.5 μg of dry extract/ml in the DPPH test; IC50 = 69.8 ± 3.1 μg of dry extract/ml in the β-carotene–linoleic acid test) in herbal tea of Plectranthus barbatus (Falé et al., 2009). Similarily, rosmarinic acid was shown to inhibit some metabolic enzymes including

glutathione

S-transferase,

lactoperoxidase,

acetylcholinesterase,

butyrylcholinesterase and carbonic anhydrase isoenzymes (Gülçin et al., 2016). Cholinesterase, protease inhibitory and antioxidant capacities of 17 Sri Lankan medicinal plants were

21

investigated which revealed that the bark extract of Toona ciliata showed significant antioxidant capacity and marked AChE, BChE, protease enzyme inhibitory activities compared to the positive standards (Samaradivakara et al., 2016). Neuroprotective effects of Centella asiatica against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress were examined in male wistar rats. This study found that chronic treatment with aqueous extract C. asiatica significantly attenuated colchicine-induced cognitive impairment and oxidative damage (Kumar et al., 2009). In another study the extracts of 25 different plants along

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with eight isolated compounds were evaluated for their memory-vitalizing potential out of

which, Onosma nigricaule roots were found to be a strong AChE inhibitor (63.18 ± 0.56%),

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while, the highest iron-chelating capacity (50.79 ± 3.88%) was observed for n-hexane extract

of Thymus sipyleus (Senol et al., 2016). AChE inhibitory activity has been reported in many plants such as Bacopa monnieri, Withania somnifera Dunal, Embelia ribes Burm.f., Ficus religiosa L, Nardostachys jatamansi DC, Semecarpus anacardium Linn., Tinospora cordifolia

U

sMiers., Centella asiatica urban., Convolvulus pluricaulis Choisy., Mangifera indica L.

N

Stephania suberosa, Thymus sipyleus and Tabernaemontana divaricata, by several

A

investigators (Barbosa Filho et al., 2006; Ingkaninan et al., 2003; Senol et al., 2016; Vinutha et al., 2007; Whitehouse et al., 1982).

M

Ginkgo biloba has been under prevention trials for treating AD (Wang et al., 2016b). Ginkgo biloba extract (EGb 761) inhibits Aβ aggregation and protects hippocampal neurons against

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cell death induced by Aβ (Bastianetto et al., 2000; Luo et al., 2002). Ginkgo biloba extracts regulated APP metabolism towards α-secretase pathway (Colciaghi et al., 2004). The effects of wine-related polyphenols (myricetin, morin, quercetin, kaempferol, catechin and epicatechin

EP

on the formation, extension, and destabilization of β-amyloid fibrils at pH 7.5 at 37°C were examined in vitro and potential anti-amyloidogenic and fibril-destabilizing effects were observed (Ono et al., 2003). Potent anti-amyloid effects of curcumin were elucidated in vitro

CC

by several reports (Ono et al., 2004; Zhang et al., 2010). Amongst the three standardized turmeric extracts examined, HSS-888 showed strong inhibition of Aβ aggregation and

A

secretion in thioflavin T cell-free assay and the secretion of Aβ from human neuronal cells (SweAPP N2A cells) in vitro (Shytle et al., 2009). Herbal treatments in vitro have also conferred protection against Aβ-induced toxicity in various cell culture systems. Although, it is worth mentioning that curcumin has shown poor pharmacokinetics in the in vivo studies (Burgos‐Morón et al., 2010).

22

Curcuma longa extracts (Ono et al., 2004) and Withania somnifera extracts (Kumar et al., 2012) prevented Aβ fibril formation and protected pheochromocytoma cells (Park et al., 2002) and SweAPP N2A cells (Huang et al., 2008; Shytle et al., 2009) from the harm caused by Aβ oligomers and fibrils. Angelica sinensis extract exerted protective effects on amyloid βpeptide-induced neurotoxicity (Huang et al., 2008). Lycium barbarum, anti-aging oriental medicine, showed neuroprotective effects of against β-amyloid peptide neurotoxicity (Yu et al., 2005). In brain sections from AD patients and Tg2576 mice curcumin effectively blocked

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Aβ1-40 aggregation and Aβ1-42 fibril and oligomer formation. Eugenol and β-asarone derived

from Rhizoma acori graminei, rescued PC12 cells from death by blocking Aβ-induced calcium

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intake (Zhang, 2004). EGb 761-treated hippocampal slices from rat brains showed an increased release of soluble APPs (Colciaghi et al., 2004), and mutant embryonic kidney cells from

humans that were treated with huperzine A reversed the Aβ-induced down-regulation of APP

U

secretion and PKC activity (Zhang, 2004).

N

Besides complex extracts and single-herb pure bioactive compounds, mixtures of several herbs (Combinational therapeutics) have been traditionally used for treating dementia.

A

Yukmijihwang-tang (a combination of six herbs, namely Rehmannia glutinosa, Cornus

M

officinalis, Dioscorea batatas, Paeonia suffruticosa, Poria cocos, Alisma orientale) is one of the most widely used herbal formulas in Korea, China and Japan. Yukmijihwang-tang

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increased the expression of transthyretin and PEP-19, a neuron-specific protein that inhibited apoptosis in the hippocampus (Rho et al., 2005). Another traditional Chinese medicine, Naoweikang, a combination of Ginkgo biloba and Panax ginseng, increased the level of AChE in the brains of Sprague–Dawley rats following an Aβ1-40 insult (Liu et al., 2004). The Korean

EP

herbal medicine ESP-2, which contains a combination of extracts from three herbs (Angelica gigas, Saururus chinensis and Schizandra chinensis), effectively inhibited AChE activity,

CC

alleviated scopolamine-induced memory impairment in ICR mice, and protected rat neurons from Aβ or glutamate-induced neurotoxicity(Kang et al., 2005). In mouse model of AD, Kami-

A

untan-to (PubChem: 96025738), a mixture of 13 herbs used in Chinese-Japanese herbal medicine, inhibited thiamine-deficient, feeding-induced learning and memory impairment, increased choline acetyltransferase activity, and increased the survival rate of the mice (Nakagawasai et al., 2004). In the same mouse model, Zhokumei-to, a mixture of nine herbs, repaired Aβ-induced memory impairment and increased the expression of synaptophysinin the cortex and hippocampus (Tohda et al., 2004).

23

This review lists various medicinal plants reported for their nootropic properties in regard to AD phytotherapy (Table 3).

Plant Part Used

Relevance with AD phytotherapy

Reference(s)

1

Acorus calamus

Common Sweet Flag

Rhizome

Improvement in learning and memory

2

Albizzia julibrissin

Mimosa, Persian Silk Tree

Stem Bark

Anti-depressant

3

Albizzia lebbeck

Indian Siris

Leaf

Nootropic, Anxiolytic

(Chintawar et al., 2002)

4

Anemarrhena Zhi mu asphodeloides (Chinese)

Rhizome

U

Common English Name

Anti-depressant

(Lee, B. et al., 2009)

5

Angelica sinensis

Female ginseng

Root

N

S.No. Scientific Name

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Table 3: Medicinal plants reported for their nootropic properties

6

Artemisia absinthium

Common wormwood; green ginger

7

Asparagus adscendens Roxb.

A

9

10

SC R

(Kim et al., 2007)

(Huang et al., 2008)

Aerial plant parts

Restoration of memory and mental function

(Bora and Sharma, 2010)

Root

Nootropic, inhibits

(Joshi et al., 2017)

A

Protective effects against amyloid β-peptideinduced neurotoxicity

M

TE D

EP

Bacopa monnieri

acetylcholinesterase

Brahmi (Indian); water hyssop; herb of grace

Whole Plant

Nootropic, rejuvenation, inhibits acetylcholinesterase

(Aguiar and Borowski, 2013; Ramachandran et al., 2014)

Celastrus paniculatus

Black oil plant; Jyotishmati (Indian)

Seed

Improvement in memory function

(Bhanumathy et al., 2010)

Centella asiatica

Asiatic pennywort; Mandookaparni (Indian)

Whole Plant

Modulates antioxidant and (Gray et al., mitochondrial pathways 2016) and improves cognitive function

CC

8

Safed musli

(Achliya et al., 2004)

24

Clitoria ternatea

Butterfly pea; Cordofan pea; Asian pigeonwings

Aerial plant parts

Nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity

(Jain et al., 2003)

12

Commiphora whighitii

Indian bdellium-tree; Guggul (Indian)

Leaf, Stem, Root, Latex and Fruit

Anti-inflammatory efficiency, learning and memory improvement

(Bhatia et al., 2015)

13

Convolvulus pluricaulis

Shankhapushpi (Indian)

Whole plant

Nootropic, anxiolytic, (Agarwa et al., tranquillizing, 2014) antidepressant, anti-stress, neuroregenerative, antiamnesic

14

Cornus officinalis

Fruit Japanese cornelian cherry or Dogwood fruit

15

Crocus sativus

Saffron, Kesar (Indian)

Stigma

16

Curcuma longa

Turmeric; Haldi (Indian)

17

Eclipta alba

Bhringraj (Indian)

18

Eclipta prostrata

19

SC R

IP T

11

(Lee, K.Y. et al., 2009)

Anti-depressant, antistress, rejuvenation

(Noorbala et al., 2005)

Rhizome

Anti-amyloidogenic effects

(Shytle et al., 2009)

Aerial plant parts

Anticonvulsant, (Mansoorali et cerebroprotective, al., 2012) sedative, anxiolytic, antistress, nootropic, rejuvenation

False daisy

Whole plant

increases the formation of brain acetylcholine and decreases oxidative stress

(Kim et al., 2010)

Embelica officinalis

Indian gooseberry; Amla (Indian)

Fruit

Memory enhancing

(Vasudevan and Parle, 2007)

20

Evolvulus alsinoides.

Slender dwarf morning-glory; vishnukranthi (Indian)

Aerial plant parts

Adaptogenic, antiamnesic, improve learning and memory

(Nahata et al., 2010)

21

Ficus religiosa

Sacred fig; peepal (Indian)

Fruit

Anti-amnesic

(Kaur et al., 2010)

M

TE D

EP

CC A

A

N

U

Anti-amnesic

25

Foeniculum vulgare

Fennel

Whole plant

Anti-acetylcholinesterase; memory enhancer

(Joshi and Parle, 2006)

23

Galanthus nivalis

Common snowdrop

Flower

Anti-Alzheimer’s disease

(Heinrich and Teoh, 2004)

24

Ginkgo biloba Maidenhair tree

Leaf

Inhibition of Aβ-induced toxicity and cell death

(Bastianetto et al., 2000)

25

Glycyrrhiza glabra

Root Liquorice, mulethi (Indian)

Memory and cognition enhancer

(Cui et al., 2008)

26

Huperzia serrata

Toothed clubmoss

Whole plant

Anti-acetylcholinesterase; neuroprotective

27

Hypericum perforatum

St John's Wort

Leaf

Anti-depressant, antistress, antioxidant

28

Lavandula angustifolia

Lavender

Flower

Anti-Alzheimer’s disease; (Soheili et al., improves deteriorated 2015) synaptic plasticity

29

Leontopodium Edelweiss alpinum

30

Leuzea carthamoides

Russian Leuzea

31

Marsilea minuta

32

Melissa officinalis

33

SC R

(Antar et al., 2015; Li et al., 2016; Ohba et al., 2015)

N

U

(Yalçın et al., 2015)

(Hornick et al., 2008)

Seed

Anti-anxiety, selective stress-reducing effects

(Yamamotová et al., 2007)

Dwarf water clover, pepperwort

Whole plant

Anti-depressant, treats insomnia

(Yamamotová et al., 2007)

Lemon balm

Leaf

Nootropic, anxiolytic, antidepressant, anti-stress

(Lin et al., 2015)

Mentha arvensis

Pudina (Indian); Leaf wild-mint

Anti-acetylcholinesterase; neuroprotective, antistress

(Feng et al., 2015)

34

Murraya koenigii

Curry tree, meetha neem (Indian)

Leaf

Nootropic, rejuvenation, inhibits acetylcholinesterase

(Handral et al., 2012)

35

Panax ginseng

Ginseng

Root

Enhance psychomotor and (Wang, Y. et al., cognitive performance, 2016) anti-acetylcholinesterase

M

TE D

EP

CC

A

Enhancement of synaptic availability of acetylcholinesterase; Anti-dementia

A

SubAerial parts

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22

26

Passiflora actinia

Passion flower

Flower

Anxiolytic

(Sarris et al., 2013)

37

Polygala tenuifolia

Yuan Zhi (Chinese)

Root

Memory and cognition enhancer

(Cheong et al., 2011; Park et al., 2002)

38

Prunus amygdalus

Almond, Badaam (Indian)

Seed

Nootropic, rejuvenation, memory and cognition enhancer

(Guaâdaoui et al., 2015; Kulkarni et al., 2010)

39

Ptychopetalu m olacoides

Marapuama (Amazonian)

Root

Memory enhancer; Nootropic

40

Pueraria tuberosa

Indian kudzu

Rhizome

Nootropic

41

Rhodiola rosea

Golden root, rose root

Root

Alleviating mental fatigue, anti-anxiety

(Nabavi et al., 2016)

42

Rosa damascena

Damask rose, Gulaab (Indian)

Flower

Anticonvulsant, antiamyloidogenic, anticholinesterase, antioxidant, neuroprotective effects, nootropic, rejuvenation, memory and cognition enhancer

(Esfandiary et al., 2015; Homayoun et al., 2015; Senol et al., 2013)

43

Rosmarinus officinalis

Rosemary

Leaf

Anti-amyloidogenic, anticholinesterase, antioxidant, neuroprotective effects, nootropic, rejuvenation, memory and cognition enhancer

(Ozarowski et al., 2013; Perry et al., 1998; Ramachandran et al., 2014; Sasaki et al., 2013)

44

Rubia cordifolia

Indian madder, manjistha (Indian)

Root

Neuroprotective, anti(Chitra and amyloidogenic, nootropic, Pavan Kumar, rejuvenation 2009; Meena et al., 2010)

45

Salvia officinalis

Common sage

Leaf

Anti-nociceptive, antiinflammatory, antiamyloidogenic anticholinesterase, memory and cognition enhancer

(Perry et al., 2003; Rodrigues et al., 2012)

46

Salvia Spanish sage lavandulaefoli a

Leaf

Anti-amnesia

(PorresMartínez et al., 2013)

(da Silva et al., 2007; Figueiró et al., 2010)

SC R

U

N

A M TE D

EP

CC A

IP T

36

(Maji et al., 2014)

27

47

Salvia miltiorrhiza

Chinese sage

Root and Aerial parts respectiv ely

Anxiolytic

(Leung et al., 2010; Liu et al., 2015)

48

Syzygium aromaticum L.

Clove; Loung (Indian); Ding xiang (Chinese)

Clove buds

Anti-cholinesterase

(Saeedi et al., 2017)

49

Tabernaemon Pin wheel tana flower, crape divaricata jasmine, East Indian rosebay

Root, Anti-cholinesterase bark, leaf respectiv ely

50

Tinospora cordifolia

Heart-leaved Moonseed; Guduchi (Indian); Giloy (Indian)

Aerial plant parts

51

Thespesia populnea

Indian tulip tree, Bark pacific rosewood, Milo (Hawaiian)

52

Uncaria tomentosa

Cat's claw

53

Vitis vinifera

Withania somnifera

A

N

Anti-inflammatory, antiAlzheimer’s disease

M

IP T

SC R

U

Anti-amyloidogenic, anti- (Kosaraju et al., cholinesterase, 2014; Sankhala antioxidant, et al., 2012) neuroprotective effects, nootropic (Baradaran et al., 2012; Vasudevan and Parle, 2006)

Neuroprotective, antioxidant

(Tamborena et al., 2015; Zhang, 2001; Zhang et al., 2015)

Common grape vine, Angoor (Indian)

Fruit

Anticonvulsant, antiamyloidogenic, anticholinesterase, antioxidant, neuroprotective effects, nootropic, rejuvenation, memory and cognition enhancer

(Aslam and Sultana, 2015; Lakshmi et al., 2014; Srikanth et al., 2013)

Indian ginseng; Ashwagandha (Indian)

Root

Anticonvulsant, cerebroprotective, anxiolytic, anti-stress, nootropic, rejuvenation, anti-Alzheimer’s disease

(Durg et al., 2015; Mancini et al., 2016; Mishra et al., 2000; Orrù et al., 2016)

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Aerial plant parts

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54

(Alper et al., 2012; Khan and Islam, 2012; Randhava and Devi, 2015)

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55

Zingiber officinale

Ginger, Adhrakh (Indian)

Rhizome

Nootropic, rejuvenation, anti-Alzheimer’s disease, anti-amyloidogenic, anticholinesterase,

(Ali et al., 2008; Oboh et al., 2012; Wattanathorn et al., 2010)

9. Conclusion

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Alzheimer’s disease (AD) is the most common type of dementia, which is currently a global

as well as economic threat. AD is a multifactorial condition, therefore there are a number of

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therapeutic targets (Piau et al., 2011). Currently FDA-approved treatment for AD only treats

symptoms and is unable to treat the memory problems or stop the progression of AD neurodegeneration. Hence, there remains an urgent need for developing alternative approaches to AD therapeutics which targets multiple underlying pathways to obtain better treatment for

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AD. Traditional medicine systems suggest many medicinal plants may be useful for treatment

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of severe diseases like cancer, stroke, cardiovascular disorders, and neurodegenerative

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disorders. Various active compounds derived primarily from medicinal plants have been assessed for their efficacy in dementia, primarily in AD. In fact, current drugs for AD, such as

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rivastigmine and galantamine are phytochemical (alkaloids) based drugs which are selective, competitive AChE inhibitors that can be obtained synthetically or from the bulbs and flowers

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of Galanthus sp. Recently some phytodrugs have been systematically tested in animal and cell models of AD and even in clinical trials. Such studies might provide a promising lead for discovering appropriate drug(s) for AD. Ginkgo biloba, Curcuma longa, Withania somnifera, Angelica sinensis extracts have been well-known to regulate APP metabolism towards α-

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secretase pathway as well as constrain the formation, extension, and stabilization of Aβ fibrils. They also have been reported to protect against Aβ-induced neurotoxicity (Bastianetto et al.,

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2000; Colciaghi et al., 2004; Huang et al., 2008; Kumar et al., 2009; Kumar et al., 2012; Luo et al., 2002; Ono et al., 2004). Ginkgo biloba has been under prevention trials for treating AD

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(Wang, J. et al., 2016). The variability of the constituents in medicinal plants and their preparations due to genetic, cultural and environmental factors have been the major hindrance in the amalgamation of traditional plant medicines into modern medical practices. Standardization of natural resources, such as medicinal plants, has been established as the key to ensure their safety, efficacy, quality assurance, stability of finished product and effective clinical as well as industrial employment. Thus, it could be concluded that herbal drugs are relatively less toxic, bioavailable, exert multiple synergistic effects, improve cognitive and 29

cholinergic functions. Thus, herbal drugs appear to be a promising alternative medicine in treating neurodegenerative disorders and alleviating sufferings of patients. Major concerns with globalization of botanical preparations, calls for adoption of “fit-for-purpose” standardization approach according to which each case must be treated individually, and detailed research must be carried out to set the standards. However, to determine their adverse effects in AD patients further research is needed on each medicinal plant in terms of pathology

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and phenotypic behavior in well-designed clinical trials.

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Conflict of interest The authors declare no conflict of interest.

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Acknowledgements

Dr. Swati Vyas expresses her gratitude to the Department of Science and Technology, India

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for the “Innovation in Science Pursuit for Inspired Research (INSPIRE)-Fellowship”. Authors

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also acknowledge DBT-BIF facilities at University of Rajasthan, Jaipur.

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Also, inputs towards improvisation of the manuscript from Ms. Prerna Dhingra (DST-

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CC

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INSPIRE-SRF) and Mr. Sankalp Sharma are highly appreciated.

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