Part 1 Herbal Drugs And Natural Bioactive Products As Potential Therapeutics: A Review On Pro-cognitives And Brain Boosters Perspectives

Swati Halder a,1, Utpal Anand b,1, Samapika Nandy a, Patrik Oleksak c, , Safaa Qusti d, Eida M. Alshammari e, Gaber El-Saber Batiha f, Eapen P. Koshy b, Abhijit Dey a,

aDepartment of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India

bDepartment of Molecular and Cellular Engineering, Jacob Institute of Biotechnology and Bioengineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India

cDepartment of Chemistry, Faculty of Science, University of Hradec Kralove, 50003 Hradec Kralove, Czech Republic

d Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia Department of Chemistry, College of Sciences, University of Ha’il, Ha’il, Saudi Arabia

f Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt

Abstract

Memory, one of the most vital aspects of the human brain, is necessary for the effective survival of an individual. ‘Memory’ can be defined in various ways but in an overall view, memory is the retention of the information that the brain grasps. Different factors are responsible for the disbalance in the brain's hippocampus region and the acetylcholine level, which masters the memory and cognitive functions. Plants are a source of pharmacologically potent drug molecules of high efficacy. Recently herbal medicine has evolved rapidly, gaining great acceptance worldwide due to its natural origin and fewer side effects. In this review, the authors have discussed the mechanisms and pharmacological action of herbal bioactive compounds to boost memory. Moreover, this review presents an update of different herbs and natural products that could act as memory enhancers and how they can be potentially utilized shortly for the treatment of severe brain disorders. In addition, the authors also discuss the differences in the biological activity of the same herb and emphasize the requirement for a higher standardization in cultivation methods and plant processing. The demand for further studies evaluating the interactions of herbal drugs is mentioned.

For more information please contact ali.ma@wecistanche.com

Click to cistanche tubulosa benefits and side effects and Cistanche for memory

1.Introduction

1.1. Memory: Brief background

The human brain is the most complex organ in the body. One of its most impressive aspects is the ability to retain information, which is called memory (Christophel et al., 2017; Postle, 2016). Before this review work, we have to know the definition of what memory is. ‘Memory’ perhaps can be defined in various ways. An overall standard definition is: Memory is the ability of an individual to record sensory stimuli, events, pieces of information, etc. and retain them over short or long periods and recall the same whenever needed at a later date” (Zlotnik and Vansintjan, 2019). In short, memory is one of the most vital aspects for the effective survival of human beings (Shiksharthi et al., 2011). But when we discuss memory, it is not only the retention of information, along with it we also consider some associated terms like- cognition, intelligence, attention, concentration, quality of life (QOL), etc. Intelligence is according to Ayurveda the combination of three capabilities of mind:

Acquisition: Capacity to grasp any information and to analyze it.

Retention: Retain the information inside the brain.

Recollection: Recall the information later (Rathee et al., 2008). Based on the different mechanisms and types, memory can be classified into 3 types (Camina and Güell, 2017):

i) Short-term memory (STM)–rapidly formed memory that is retained for a short time (minutes to hours).

ii) Long-term memory (LTM)–a memory that is retained for long periods, e.g.-from hours to days, weeks, months, even years. (Rho et al., 2005).

iii) Sensory Memory or Iconic Memory-the potential to remember temporarily the huge amounts of information that people experience every day The up-mentioned ‘retention’ and ‘recollection’ deal with STM and LTM respectively (Rathee et al., 2008).

1.2. Storing of memory inside the brain

When we are discussing memory, we have to know the mechanism by which various kinds of information are stored inside our brains. There is a region in our brain, named ‘Hippocampus’, located in the medial temporal lobe of the brain. This hippocampus is the center of all these memory and cognitive functions. At first, our brain cells grasp whatever we see, hear or do; then the hippocampus decides whether the information we grasped is important to store or not; if the hippocampus decides to store the information, it retains inside our brains and we can memorize it, otherwise, the information gets deleted from our brain automatically (Shiksharthi et al., 2011; Kandel et al., 2014). This mechanism involves the interaction between various neurotransmitters in the brain (Shiksharthi et al., 2011; Shefflfler and Pillarisetty, 2019). Acetylcholine (ACh) is the most important neurotransmitter.

involved in memory and cognitive functions apart from several neurodegenerative pathogenicities (Parle and Vasidevan, 2007; Akaike et al., 2018). One important enzyme involved in this mechanism is Acetylcholinesterase (AChE). Estimation of this enzyme’s activity is an important parameter to assess the central cholinergic function. Acetylcholinesterase (AChE) modulates proper levels of acetylcholine by breaking ACh into Choline (the building block of ACh). However, the excessive activity of AChE results in the deficiency of ACh, leading to memory impairment (Rathee et al., 2008; Shiksharthi et al., 2011).

1.3. Memory impairment

Poor memory, low retention power, difficulty to recall, lack of concentration, weak analyzing ability-these are very much common problems of the modern world. Besides some of the conditions, such as stress, aging and emotions may lead to memory impairment, amnesia, dementia, etc., and sometimes to some serious threats like Alzheimer’s disease (AD), Schizophrenia, etc. (Gur and Gur, 2013; Hildebrandt, 2019). In AD, the function of the hippocampus is destroyed, so that the brain cannot manage to store different kinds of information, especially the new ones. Besides, the neurons start to get degenerated. This disease affects mostly the elderly population, aging 65 years or more (Wortmann, 2015; Winblad et al., 2016; Alzheimer’s Association, 2016). According to the cholinergic hypothesis, memory-impaired due to deficiency in the cholinergic function inside the brain. Cognitive dysfunction is correlated with this impaired cholinergic function (Dumas and Newhouse, 2011; Bohnen et al., 2018).

1.4. Memory enhancers

Functional foods, supplements, and drugs that can improve memory, cognition intelligence, and other mental functions are known as memory and cognitive enhancers (Lynch et al., 2014; Morè et al., 2020). There is another term that can be used to describe memory and cognitive enhancers: ‘Nootropics’ (Pieramico et al., 2014; Onaolapo et al., 2019). Nootropics. The word ‘nootropic’ (Greek: nous-mind, tropein-to bend/turn or monitor) was first coined in 1972 by Dr. Corneliu E Giurgea. Nootropics are referred to as ‘smart drugs’ that act upon our brain cells. A nootropic is an extremely non-toxic neuroprotective substance and can be used as a memory and cognitive enhancer and in AD treatment (Colucci et al., 2012; Chaudhari et al., 2017). The functions of nootropics are: (a) Improving Acetylcholine level in the brain, (b) Improving O2 supply to the brain, (c) Supplying neurochemicals (e.g.-neurotransmitters, enzymes, hormones) to the brain (Jeon, 2015; Suliman et al., 2016; Crespo-Bujosa and Rodríguez, 2019). To improve memory and mood several nootropic agents are generally used such as Aniracetam, Oxiracetam, Pramiracetam, Piracetam, and Choline esterase inhibitors like Donepezil, but the side effects of these agents (Talih and Ajaltouni, 2015; Zaami et al., 2020) have made their applicability limited.

1.5. Herbal remedies for impaired memory and cognition: Mechanisms and pharmacological actions

Herbal remedies are traditionally used all over the world to enhance poor memory and related ailments (Giampieri et al., 2014; Liao and Lin 2012; Banerjee et al., 2021; Gregory et al., 2021). Several medicinal plants and their extracts have shown nootropic properties or memory-enhancing properties by the suitable character of their medicinal components (Aguiar and Borowski, 2013; Onaolapo et al., 2019; Banerjee et al., 2021; Tandon et al., 2021). The increasing demand for herbal remedies worldwide is because herbal compounds have lesser or no side effects than any other chemical compound (Anand et al., 2019). Our very own Indian Ayurveda possesses a treasury of such medicinal plants that enhance memory, cognition, and intelligence. These Ayurvedic herbs are now popular all over the world (Anand et al., 2019). Not only Indian Ayurveda, the Traditional Chinese Medicine (TCM), Japanese, Korean, African, American, and European medicines also come with a huge number of medicinal plants helping in reversing memory impairment. The herbs acting upon brain cells are termed ‘nootropic herbs/drugs’ and their isolated compounds are called ‘smart drugs’ or ‘cognitive enhancers or ‘brain booster’ (Hildt, 2013; Frati et al., 2015). According to Ayurveda, herbs that promote intelligence is known as ‘Medhya herbs/ Rasayana’ (Kulkarni et al., 2012; Reena et al., 2013) and includes 10 herbal drugs namely Jatamansi, Ashwagandha, Vacha, Jyotishmati, Shankha-pushpin, Amalaki, Yashtimadhu, Kavach Beej, Bramhi, and Mandukparent (Lele, 2010). All these medicinal herbs increase the neurotransmitter level (especially acetylcholine) in the brain by inhibiting excess AChE activity and also improving blood circulation inside the brain thus providing a sufficient supply of O2 to the brain cells (Colovic et al., 2013; Suliman et al., 2016). Some home remedies against poor memory are found in commonly known food plants, which we can have as oils and vegetables (Fernando et al., 2015; Hardman et al., 2016; Molz and Schröder, 2017). The World Health Organization (WHO) states that at present date 80% of the world population are using herbal remedies for the improvement of health (Srivastava et al., 2019)

1.6. History of memory enhancers in Ayurveda and TCM

Ayurveda, the science of life is a long traditional alternative medicine system from the Indian subcontinent. This natural science is based on the fundamental laws of nature with therapeutic approach for treatment of innumerous human diseases. Aging represents a systematic involution of the human body and the brain is considered as the most vulnerable organ to this process. Therefore, to avoid this damage, the Rasayana therapy, a rejuvenation branch of Ayurvedic medicine was established. Various natural drugs that act as brain tonic, promote health of the brain, lead to the alleviation of behavioral disorders or improve memory impairment are utilized in Rasayana approach. Various memory enhancing and rejuvenating plants are used in Rasayana therapies, including: Acorus calamus, Bacopa monniera, Clitoria ternatea, Nardostachys jatamansi, Terminalia chebula and many others (Singh 2013). Traditional Chinese medicine (TCM) is based on the balance between health and disease. According to theory of TCM, healthy body is the body in the balance, on the other hand disharmony is not the cause of disease. The disease is caused by life style, influence of pathogens and various negative effects. However, the balance can be restored by herbal treatment. For over thousands of years, Chinese people have accumulated experiences in treatment, diagnosis, and disease prevention to create a whole theoretical system of medicine therapy. Herbal medicines with memory enhancing properties are also encompassed in the TCM. Between the plants used in TCM for memory improvement belong: Huperzia serrata, Ginkgo biloba, Panax ginseng, Camellia sinensis and other (Yan et al., 2007). These and above-mentioned plants will be discussed in following sections.

2. List of herbs having memory and cognition-enhancing properties

2.1. Family AcoraceaeAcorus calamus L. / Sweet L flag is a medicinal valuable semiaquatic herb that grows throughout India, Central Asia, Siberia,

Eastern Europe, Southern Russia, and could be found in gardens too. This perennial plant is not frost-tender and grows to a height of 1 m. It shows numerous therapeutic properties such as antiproliferative, anti ulcerative, antibacterial, antioxidant, insecticidal, immunosuppressive, antifungal, etc. (Pandit et al., 2011; Kumar et al., 2012; Parki et al., 2017). A plethora of bioactive chemical constituents like b-asarone (40) (AChE inhibitor) (Mukherjee et al., 2007a), phenylpropanoid, saponins, lectins, flavonoids, sesquiterpene, alkaloids, a-asarone (67), phenols, monoterpene, and quinones, mucilages, etc. are exhibited by this plant (Joshi, 2016). The rhizome of this plant ‘Acorn Calami Rhizoma’, is mainly used to enhance/improve memory (May et al., 2016). Sweet L flag is a very essential brain tonic as it shows very short time results. Articles claiming this herb to cure AD are out (Nandakumar et al., 2013). Sweet flag strengthens the nervous system and increases the overall memory of the person. This is prescribed to patients who have epilepsy, amnesia, hysteria, insomnia, neurosis, remittent fevers, and melancholia (Huang et al., 2013; Sharma et al., 2014). The sweet flag contains essential oil in which 67 and 40 are present as the main components, which harbor anti-inflflammatory properties to downregulate inflammatory cytokines (Shin et al., 2014; Lim et al., 2014).

2.2. Family Apiaceae

Centella Asiatica (L.) Urban / Gotu kola (also known as Than-kuni) is native to the wetlands in Asia and is widely scattered across the subtropical regions tropical geographical regions of India, Indonesia, Madagascar, China, Sri Lanka, and Nepal. This evergreen perennial plant is self-fertile, frost-tender, and grows to a height of 20 cm. It is commonly used as a green leafy vegetable and as a medicinal herb in AM, Unani Medicine (UM), Traditional African Medicine (TAM), and TCM (Jahan et al., 2012). It contains a wide array of phytochemicals, which include flavonoids, tannins, triterpenoids (Asiatic acid, asiaticoside, madecassic acid, and madecassoside), glycosides, essential oils, alkaloids, and volatile fatty acids (Das, 2011). It effectively enhances blood circulation in different body parts including the brain. Moreover, it helps to protect the brain from damage and improves concentration. The brain is more receptive to information and the memory is enhanced (Mannangatti and Naidu, 2016). The usage of this herb is documented over the centuries in the Indian medicine system for the treatment and prevention of several diseases and health-related ailments including cancer wound healing, dementia, diabetes, skin problems, ulcers, for regenerating the brain and nerve cells, for combating aging, asthma, (Singh et al., 2010; Sabaragamuwa et al., 2018) (Fig. 1). The positive results of Centella Asiatica on the general ability, power of concentration, and behavior of mentally retarded children have been found in pharmacological and clinical trials. It is proposed that Centella Asiatica and Bacopa monnieri have the similar medicinal value. A nervine tonic for the treatment of various brain diseases or syrup to increase the memory of children is prepared from the whole plant. C. Asiatica also inhibits scopolamine-induces memory impairment through the inhibition of AChE enzyme activity (Orhan et al., 2013). An animal study on mice model has shown asiaticoside as a neuroprotective agent and this effect could be linked with asiaticoside’s antiinflflammatory activity by inhibition of the overactivated p38 MAPK pathway (Chen et al. 2014). In middle cerebral artery occlusion (MCAO) rats, the ethanolic extract of C. asiatica has demonstrated to be enhanced neurobehavioral activity, educed infarction volume along with preserved brain neuroanatomy, increased the status of antioxidants and decreased the levels of free radicals (Tabassum et al., 2013). In vitro experiment of water extract of this herb preserved/protected human neuroblastoma MC65 cell line and SHSY5Y cells from b-amyloid toxicity (Soumyanath et al., 2012). Recently, in vitro examination of C. asiatica leaf extract signifificantly suppressed a-synuclein aggregation and prevented oligomer formation of aggregates that suggested the therapeutic potential of C. asiatica against Parkinson’s disease (PD) (Ruben et al., 2014).

2.3. Family Aquifoliaceae

Ilex paraguariensis (A.) St.-Hil. / Yerba mate is plant typically growing and processing in South America, especially in northern Argentina, Paraguay, Uruguay and southern Brazil (Bracesco et al., 2011). This evergreen tree/shrub growing up to height of 15 m has simple obovate-oblong leaves, 4-membered small green-white flflowers and small red drupe fruits with diameter of 4–6 mm. It is traditionally used for a preparation of the beverage called mate, which possesses high nutritional values. I. paraguariensis extract contains polyphenols (chlorogenic acids), tannins, xanthines (caffeine, theophylline and theobromine), flflavonoids (quercetin (80), kaempferol), purine alkaloids (methyl xanthines), saponins, and vitamins (A, C, B1, B12, E) (Bracesco et al., 2011). It’s entry into the body exhibit neuroprotective, diuretic, antimutagenic, anti-inflflammatory, antioxidant, antidiabetic, antihyperglycemic, antidepressant, anticonvulsant, hypocholesterolaemic, antifungal, anti-obesity effects (Fernandes et al., 2017). The memory-enhancing activity of mate tea leaves are reported on different models of memory and learning (Prediger et al., 2008). The worthwhile effects of mate tea used for the enhancement of cognition, short- and long-term memory in animals were reported. It also has properties to treat dementia. More recently, several groups of researchers have demonstrated that I. paraguariensis derivatives are abundant with bioactive compounds which when enters CNS and produces signifificant therapeutic indices (Cittadini et al., 2019). Leaves aqueous extract of this medicinal herb has been shown to potentially inhibit scopolamine-induced memory loss in male Swiss mice (Santos et al., 2015).

2.4. Family Araliaceae

Panax ginseng C.A.Mey. / Ginseng grows only in the NorthernHemisphere, typically in cooler climates of North America andeastern Asia (northeast China, eastern Siberia, Korea and Bhutan).It is a perennial, hermaphrodite herb which grows to a height of80 cm, has green-white small (3 mm) flflowers and oval-shapedred drupe fruits, 6–7 mm long. This herb has a signifificant application in TCM for thousands of years. It is used mostly as a memorytonic and to improve memory and learning, especially in elderlypeople. It contains saponins that enhance memory in thescopolamine-induced learning impairment. It is proposed thatthe main active components in Ginseng roots, Ginsenosides (Rg1(20), Rg2 (21), Rg3 (30), Rh2 (22) etc), induce in the central cholinergic nervous system the enhancement of choline uptake, which isimportant for learning and memory. In rats, the cyproheptadineinduced recognition defificits were improved by a component of ginseng saponin.

2.5. Family Asteraceae

Eclipta alba (L.) Hassk. / Bhringaraj grows commonly in moist places and called as a weed by the farmers all over the world. This annual herb growing to a height of 30–40 cm, has cylindrical roots and white flflowers 6–8 mm in diameter. It is widely distributed in tropical areas worldwide e.g. in India, China, Bangladesh, Thailand, and Brazil. Wedelolactone, luteolin, ursolic acid, apigenin, eclalbasaponins, and oleanolic acid are some of the potential bioactive constituents of this plant. E. alba possesses multifunctional pharmacological properties and has proven benefificial effects in the treatment of various disorders including cancer, gastrointestinal disorders, malaria, fever, snake bite, cuts and wounds, skin disorders, arthritis, respiratory tract disorders (like asthma), inflflammation, graying of hair and hair loss, liver disorders (like jaundice), microbial diseases, and spleen development (Jahan et al., 2014). Bhringaraj is traditionally used for its memory enhancing quality, and thus it is not suprising that several studies were conducted for this purpose. Dose of 100 and 200 mg/kg of the Bhringaraj leaves aqueous extract was administered to rats. Then transfer latency (TL), which represents a measure of acquisition and retrirval learning was evaluated on an elevated plus-maze test. The spatial habitual learning revealed a relevant advancement in retrieval memory of tested rodents (Banji et al., 2007; Bhaskar and Chintamaneni, 2014). Notably, the antiepilepsy activity of E. alba phytoconstituents (wedelolactone, b-amyrin, and luteolin) have been widely reported by several groups of researchers (Shaikh et al., 2012; Shaikh et al., 2013).

2.6. Family Caprifoliaceae

Nardostachys jatamansi (D.Don) DC. / Jatamansi is well-reputed Medhya herb that has a place of respect in the IndianAyurveda. This small perennial flflowering herb grows to a heightof 10–50 cm and has bell-shaped pink flflowers. It commonly growsin the Himalayas of Nepal, China and India. Ayurveda says the rootsof Nardostachys jatamansi have anti-ischemic, antioxidant, anticon-vulsant and neuroprotective activities. The ethanolic extract ofJatamansi at a dose of 200 mg/kg b.w. signifificantly lead to theimprovement in learning and memory power in young mice. Moreover, the scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.)-induced amnesia was considerably reversed. It also reversedthe natural ageing-induced amnesia in mice. From these results,it can be said that Jatamansi might prove to be a useful remedyfor the treatment of dementia in elderly persons.

2.7. Family Celastraceae

Celastrus paniculatus Willd. / Jyotishmati (also known as Kan-gani and Malkangni) belongs to the genus of woody, climbing shrubs. The stems are up to 10 m long and twine into the surrounding vegetation. Pale brown bark is covered with small elongated lenticles. The leaves are simple, broad and oval with toothed margins. Jyotishmati, one of the most widely explored medicinal plant and well known Medhya Rasayana’ (nervine tonic) in Ayurvedic medicine (AM) (Malik et al., 2017). It is distributed in various geographical locations including Southeast Asian countries like Thailand, Sri Lanka, Nepal, Japan, Myanmar, China, India, Malaysia, Taiwan, Indonesia, Vietnam and Australia (Mishra 2011) at elevations up to 10–18 m height. The seeds and seeds oil is the main part of this plant that contains a plethora of phytochemicals including triterpenoid pristimerin, sesquiterpeniod polyalcohols esters (celapnin, polyalcohol A–D, malkanguniol, malkangunin), polyalcohol (paniculatusdiol, malangunin, malkanguniol and malkanginnol), alkaloids celastrine, paniculatin, calapagine, celapanine, calapanigine, sesquiterpenes, sterols (b-amyrin and b-sitosterol), saturated fatty acids (palmitic, stearic and lignoceric acid), unsaturated fatty acids (oleic, linoleic and linolenic), phenolic triterpenoids (paniculatadiol, celastrol), lipids etc. (Katekhaye et al., 2011). They have a bitter taste, an unpleasant odour and are regularly used as neuroprotective properties, cognitive disorders, and to sharpen/enhancing the memory and boosting intelligence (Bhanumathy et al., 2010; Arora and Pandey-Rai 2014). Whole plant extract of C. paniculatus has demonstrated antiepileptic function (Atigari et al., 2012). The seeds and the seed oil are commonly used as a brain tonic, in many central nervous system (CNS) disorders and as neuro-protective agent (Bhagya et al., 2016; Malik et al., 2017). The seed oil improved learning and memory whereas the levels of dopamine, noradrenaline and serotonin were decreased in the brain of rats. The oil of this plant signififi- cantly decreases AChE activity (Bhagya et al., 2016; Malik et al., 2017). In addition to neurological benefifits, different plant parts of C. paniculatus has potentially shown to exhibit potent activity in wound healing, hypolipidemic, antioxidant, analgesic, antiinflflammatory, stomach ulcers, dyspepsia (Palle et al., 2018).

2.8. Family Combretaceae

Terminalia chebula Retz. / Haritaki is a deciduous tree, which grows in Southeastern Asia (India, China, Sri Lanka, Malaysia, and Vietnam). The tree grows to a height of 30 m, the leaves are oval with an opposite or alternate arrangement. The yellow followers occur in terminal spikes or short panicles and emit unpleasant odors. The ovoid fruits are yellow to orange-brown. The ripe fruit of Terminalia chebula is valued due its benefificial health effects includingmemory and intellect enhancement. Further, it is believed thatconsumption of the fruit is effificient to prolong life, to improve eyesight and can delay ageing. To achieve the desired effects, consumption of one ripe fruit every morning is recommended.

2.9. Family Convolvulaceae

Convolvulus pluricaulis Choisy / Shankhpushpi (also known as Bindweed) is a well-reputed Medhya herb commonly found in southern India and Burma. This perennial herb has 10–40 cm long stems and small (5 mm) blue color flflowers. In ancient times, it was a prominent memory-improving drug, a psychostimulant and tran-quiliser in traditional Indian medicine (Shethiya and Mishra, 2010). A brain tonic is prepared from the whole plant and is used for memory and intellect improvements. Its consumption also claimed to prevent memory loss. The plant contains diverse phytochemicals including b-sitosterol, vitamin C or ascorbic acid (23), silane, decanoic acid, carbohydrates, vitamin E, valeric acid or pentanoic acid, cinnamic acid, squalene, linoleic acid, phthalic acid, gums, proteins, mucilages, several alkaloids (tropane), flflavonoids (Kaempferol), and glycosides etc. as active chemicals that bring about its diverse benefificial pharmacological effects (Agarwa et al., 2014). Several groups of researches have shown that bioactive compounds of this herb displayed anti-ulcerogenic, neuroprotective, antimicrobial (anti-bacterial, antiviral), antioxidant, antianxiety, nootropic, anxiolytic, antiobsessive, anticonvulsant, antithyroid, hepatoprotective, antidepressant, hypotensive, anxiolytic, ameliorative property (Ravichandra et al., 2013; Rachitha et al., 2018; Anupama et al., 2019). In a preclinical study, the ethanolic extract of Convolvulus pluricaulis (in two doses- 100 mg and 200 mg per kg b.w.) reversed scopolamine-induced amnesia in rats (Nahata et al., 2008). Clinical studies of its polyherbal formulation justifified its potential for the ancient claim of brain tonic. The memory enhancing and learning behavior properties of Shankphapushpi have become increasingly popular worldwide in recent years. Most recently, an aqueous extract of C. pluricaulis has demonstrated to the downregulated s protein level, enhances locomotor defificits and increases longevity in human microtubule-associated protein tau (hMAPs) induced Drosophila AD model (Anupama et al., 2019).

2.10. Family Cornaceae

Cornus offificinalis Siebold & Zucc. / Japanese cornel is a deciduous tree widely spread/occurs in China, Japan and Korea. The tree grows to a height of 10 m, has a brown-gray bark and ovate leaves are 5–12 cm long. The followers are bright yellow on bare stems in late winter or early spring. Fruits are red edible berries about 1.5 cm long. This plant is usually used as a food or due to its medicinal properties (Ma et al., 2014). A plethora of phytoconstituents is exhibited by C. Officinalis including anthocyanins, flavonoids (quercetin), and phenolic acids (trans-cinnamic acid, benzoic acid), triterpenoids, anthocyanin, carbohydrates (Rudrapaul et al., 2015). Furthermore, this herb is known to harbour neuroprotective, antitumor, antidiabetic, immunomodulatory, cardioprotective, anti-amnestic, antimicrobial, antioxidant, anti-inflflammatory, renal and hepatic protective, antiosteoporotic and insecticidal property (Czerwin´ ska and Melzig, 2018). Cornel iridoid glycoside (CIG) is the main component in this herb, which has the ability to promote neurogenesis and to improve neurological function after ischemia in rats. Iridoids of C. Officinalis also protect hippocampal cells that have suffered from glutamate (Jeong et al., 2012). Further assays in rats proved, that CIG treatment signififi- cantly improved the memory defificits seen in Fimbria-fornix transaction (FFT). It also reduced the loss of neurone in the mouse hippocampus (Zhao et al., 2010). Many polyphenolic compounds obtained from C. offificinalis fruits, e.g. tellimagrandin I, tellimagrandin II and isoterchebin, are important regulators of certain enzymes and downregulate total enzymes implicated in the development of AD neurodegeneration (Bhakta et al., 2017). The documented neuroprotective and anti-amnestic property of C. offificinalis is attributed because of antiozidant and radical scavenging effects (Cooper and Ma, 2017; Huang et al., 2018).

2.11. Family Fabaceae

Desmodium gangeticum (L.) DC. / Shalparni is widely used in Ayurvedic medicine. This small shrub grows to a height of 1.2 m. The oblong leaves are simple with an alternative arrangement. The purple-white flflowers have a bilateral symmetry. D. gangeticum has traditionally been used as astringent, anthelmintic, diuretic, laxative, antipyretic, and in the treatment and prevention of neurodegenerative diseases like dementia and mental disorders (Ma et al., 2011). Signifificant bioactive phytochemicals of this plant include flflavonoids, alkaloids, terpenoids, phenolic compounds, and steroids. Furthermore, D. gangeticum has been documented to display immunomodulatory, antidiabetic, antioxidant, antimi-crobial, anti-writhing, anti-inflflammatory, renal-protective, antiulcer, hepatoprotective, antileishmanial, wound healing, and cardio-protective properties (Bhattacharjee et al., 2013). In laca mice, the alkaloid-rich fraction of D. gangeticum greatly reversed the scopolamine-induced amnesia at the dosage of 50 mg/kg (Mahajan et al., 2015). Salparni in mice signifificantly improves learning and memory abilities and reverses the scopolamine or natural ageing induced amnesia. It also decreases acetylcholinesterase activity in brain. Hence, D. gangeticum bears notable potential to its medicinal application for memory improving as well for the treatment of dementia and AD. Glycyrrhiza glabra L. / Licorice is a legume that is native to Southern Russia and Asia, Mediterranean region and is broadly planted throughout the Middle East and Europe. It is a perennial plant which grows to a height of 1.2 m. The herb has a compound leaves about 7–15 cm long, purple to pale-blue flflowers long about 0.8–1.2 cm and produces oblong pods with several seeds. This herb is known worldwide for its various curative properties. G. glabra contains diverse phytochemicals, which are of high medicinal value including flflavonoids (liquiritin, liquiritigenin, rhamnoliquirilin, isoliquiritin, etc.), triterpenes (glycyrrhizin or glycyrrhizic acid, glycyrrhetinic acid monoglucuronide), isoflflavonoids (Dehydro-glyasperin C), saponin, tannins, glycosides etc. (Batiha et al., 2020; Han et al., 2020). Various parts of this plant have been used in the treatment of various health-related disorders such as roots in diabetes, flflatulence and Graves’ disease, stem in tuberculosis, and leaves in wounds. Furthermore, this perennial herb has been widely acknowledged to treat various pathological conditions including epilepsy, stomach ulcers, jaundice, respiratory disorders, fever, hyperdipsia, hemorrhagic diseases, rheumatism, sexual debility, paralysis, skin diseases etc. Licorice, a root extract of G. glabra is generally used as a brain tonic and a brain re-vitalizer. This plant is termed in Ayurveda as ‘Medhya dravya’ and it was commonly utilized to improve memory and intellect. The assays on mice confifirmed, that aqueous extract of liquorice at the dose of 150 mg/kg signifificantly boosts memory and learning skills. Furthermore, diazepam (1 mg/kg i.p.) and scopolamine (0.4 mg/kg i.p.) induced amnesia was signifificantly reduced by liquorice extracts. Liquiritigenin (LIQ), a bioactive compound of G. glabra root has shown to inhibit glutamate-induced hippocampal neuronal cell death by downregulating ROS production, Ca2+ inflflux and lipid peroxidation, protected mitochondria from stress and MAPKs phos-phorylation (p38) thereby LIO is attributed as a strong neuroprotective agent and could be a possibility to become a potent drug for AD and PD (Yang et al., 2013).

2.12. Family Ginkoaceae

Ginkgo biloba L. / Ginkgo is a living fossil, native to China and Japan. It is a large deciduous tree growing up to a height of 35 m. The leaves are fan-shaped with two lobes, in antumn turn yellow and fall sometimes within a short period of time (1–15 days). Seeds are edible. EGb761, Ginkgo biloba leaves extract is famous globally for its beneficial pharmacological effect on neurotransmitter systems particularly in treating neurological disorders. EGb761 contain terpenoids (e.g., bilobalide, ginkgolides (28)) and ginkgolides A (13), B (14) (Fig. 2), C, J, and M, flflavonoids (e.g. kaempferol, quercetin (80) and polymeric flflavonoids) (Yuan et al., 2010). Among these, ginkgolides, a bioactive constituent of EGb761 has proven to interact with the cholinergic system and have neuroprotective and neural stem cells (NSCs) regenerative potential (Wang and Han, 2015; Ren et al., 2019). Ginkgo improves circulation of blood into the central nervous system and increases the distribution of nutrients and oxygen into the brain. It also eliminates free radicals in the body thereby improves memory and alertness. The ginkgo extract is prescribed for the treatment of amnesia and AD. Ginkgo is used as one of the important compounds in several herbal nerve tonics. Recently, this plant has demonstrated a positive effect on many neurological related health ailments including depression, psychosis, anxiety, and schizophrenia (Kumar et al., 2017). In clinical practice, Ginkgo biloba extract (GBE) has proven to treat cognitive disorders, memory impairment, AD and coronary heart disease and showed therapeutic effects at the biochemical and pharmaco-logical levels (Vellas et al., 2012; Jahanshahi et al., 2012; Zhang et al., 2013). The extract is widely used to treat AD and cerebrovascular disease (CD) (Zhang et al., 2017). Notably, during cerebral ischemia (CI) bilobalide (BB) has proven to exhibit neuroprotective effects (Huang et al., 2012). Hence, From the molecular point of view, EGb761 display antioxidant activity and downregulating tau hyperphosphorylation in addition to the protection against Ab-induced neurotoxicity and hence it could be a potential medication for treating AD.

2.13. Family Hyperiaceae

Hypericum perforatum L. / St. John’s wort is native to subtropical and temperate geographical regions of Europe, western Asia, Middle-East India, northern Africa, Russia and China. This perennial self-fertile flflowering plant grows up to a height of 1 m. It has woody stems near the base, the leaves are oblong, narrow, and about 1–2 cm long. The fifive petal flflowers are about 2.5 cm wide and colored bright yellow. H. perforatum is approved for therapeutic intervention (Bozˇin et al., 2013) and contains diverse phytochemicals such as flavonoids derivatives (rutin, amentoflflavone, hyperoside, quercetin (80), biapigenin, isoquercitrin, kaempferol, etc.), phenolic compounds, acylated phloroglucinols (hyperforin and derivatives), and naphthodiantrones (hypericin and derivatives) (Russo et al., 2014; Oliveira et al., 2016). These phytochemicals confer an array of pharmacological properties such as antiviral, neuroprotective, antifungal, anti-ischemic, wound-healing, antibacterial, antioxidant, and antideprssant activity. In SH-SY5Y neuroblastoma cells, rutin prevents accumulation and cytotoxicity of b-amyloids, mitigates mitochondrial damage, ROS, oxidative stress, and reduces nitric oxide and proinflflammatory cytokines production (Wang et al., 2012). It is an excellent tonic for brain damage and ameliorates spatial memory and learning behaviour against Ab25–35-induced toxicity (Liu et al., 2013). It helps to regenerate the nervous system, specififically the myelin sheath that surrounds nerves. Possibly, the usage of Hypericum extract could be more benefificial for the treatment of depression associated with dementia than other antidepressants that may cause sedation.

2.14. Family Iridaceae

Crocus sativus L. / Saffron dried red–orange stigma (the only usable part of this plant) is well-known as a fruit colouring, flflavoring agent, and exhibit benefificial biological/pharmacological effects. It is a flowering perennial plant which forms small brown compact corms that are flat on the base. The plant grows to a height of 10– 25 cm. The purple flflowers do not close during the night. The followers consist of six petals, three stamens, and three stigmas. The red–orange stigmas are 2.5–3 cm long and using as a noble spice. Saffron is the world’s most expensive regularly used dietary spice (Moore et al., 2012). It is a native herb in Southwest Asia (Iran). The main bioactive chemical constituents are a-crocin (47) (C44H64O24), crocetin (70) (C20H24O4), picrocrocin (C16H26O7), safranal (81) (C10H14O), water-soluble carotenoids (crocins), vitamins (thiamine and riboflflavin), carbohydrates, low concentration of monoterpene aldehydes and its glucosides (81 and picrocrocin), lipids, polypeptides, proteins, flflavonoids (quercetin (80), kaempferol, isorhamnetin and anthocyanins e.g. petunidin, malvidin, and delphinidin), starch, amino acids, gums, and minerals (Goupy et al., 2013; Zeka et al., 2015). For centuries, saffron has been extensively used as anxiolytic activity, antitussive, antibacterial, antiinflflammatery, hypolipidemic, antifungal, anti-diabetic, anticonvulsant, antityrosinase, anti-neuropathic pain, anticancer, antitussive, antioxidant, antiseptic, antidepressant, antinociceptive, anti-cancer, anti-tumor, liver and spleen enlargement prevention, S. Halder, U. Anand, S. Nandy et al. Saudi Pharmaceutical Journal 29 (2021) 879–907 885

lumbar pain remedy, chemoprotective, renal ischemia-reperfusion prevention, anti-genotoxic, an aphrodisiac, antispasmodic, tension relieving, expectorant, cardiovascular protective, antidote against poisoning, dysentery, cataract, measles, pre-eclampsia treatment, withdrawal syndrome inhibition, wound healing, and abscesses (Hosseinzadeh, 2014; Moshiri et al., 2015; Ghasemi et al., 2015). In addition to its historical value as a food additive, several studies recently indicated its potential use as neuroprotective (antiAlzheimer, anti-Parkinson), learning and memory enhancer, anxiolytic and hypnotic, against cerebral ischemia, memory defificits and brain damage, against morphine dependency mitigation (Hosseinzadeh et al., 2012; Tashakori-Sabzevar et al., 2013). Moreover, enhancing disease in adjuvant-induced arthritis, minimizing oxidative damage to the kidney (Zamani et al., 2015). These compounds signifificantly reverse scopolamine-induced amnesia. A study reveals that the treatment of mild-to-moderate AD with Saffron is safe and effective in adults ageing 55 years or more (Akhondzadeh et al., 2010). Recently, a study on adult male Wistar rats administered with aqueous extract of saffron demonstrated that saffron signifificantly upregulated brain-derived neurotrophic factor (BDNF) (both transcriptomics and protein levels) and cyclic-AMP response element binding protein (CREB) (only protein levels) in the hippocampus which manifestate that saffron could be a potential lead molecule for AD treatment (Ghasemi et al., 2015).

2.15. Fasmily Lamiaceae Melissa offificinalis L. / Lemon balm is a perennial lemonscented herb, which grows naturally in south-central Europe and the Mediterranean region. The herb is not frost tender and grows to a height of 70 cm. During summer, the white flflowers appear. Although they are small and inconspicuous, honey bees love them. The tea prepared from this plant is used in TCM to calm nerves, for its spasmolytic effects (Kumar et al., 2013) and used in European medicine to improve senses and memory. It also strengthens brain cells and clears the head. Monoterpenes such as citral and citronellal are included in the essential oil of Melissa Officinalis, which inhibits the AChE in a dose-dependent manner. Randomized, placebo-controlled, balanced-crossover and double-blind studies confirmed the influence of acute administered lemon balm on the modulation of mood and cognitive performance. It also shows a signifificant effect on people having severe dementia. Different studies show that Lemon balm has the potentials to manage the AD and to control agitation in AD patients (Kumar et al., 2013).

Ocimum tenuiflflorum L. / Tulsi (also known as ‘holy basil’) is anaromatic plant belonging to the family Lamiaceae. This well-branched perennial herb grows up to a height of 1 m. The ovate,long and slightly toothed leaves are green or purple color. Thesmall purplish orr white flflowers are placed on terminal spikes. Itis indigenous to the Indian Subcontinent and cultivated throughoutthe Southeast Asian tropics. Tulsi holds a place of respect sinceancient times in India. The whole plant extract reverses the amnesia induced by scopolamine (0.4 mg/kg) and diazepam (1 mg/kg) inmice. It also reverses the memory deficits induced by ageing. Theextract from Ocimum tenuiflflorum decreases transfer latency andincreases step-down latency in mice (in EPM test and PA paradigms as an exteroceptive behavioural model), in comparsion withcontrol (treated with piracetam), scopolamine and age groups.

Salvia lavandulaefolia Vahl / Spanish sage is a perennial plantin family Lamiaceae. It is an evergreen shrub which grows to a

height of 30 cm. The leaves are in opposite arrangement and contain essential oil with fragrance similar to rosemary. The small flowers are purplish and very attractive to bees. This small woody herb grows typically in rocky soil in the Mediterranean region(Spain and southern France). This herb become popular due itsworthwile effects on depression, cerebral ischemia, memory disorders and anticholinesterase activity. The essential oil of Salvia contains 1,8-cineole, linalool, carvacrol and luteolin. Based on clinical data, the essential oil and extracts from Salvia lavandulaefolia suggested the potential for the therapy of AD and other memory-related disorders.

Salvia offificinalis L. / Common sage is evergreen, perennial herbgrowing to a height of 60 cm. The oblong leaves are rugose, 6.5 cmlong, and are green-gray color. The flflowers are placed in spike andcan be purple, pink, whire or red. The plant is native to theMediterranean area, however due its popularity it is now cultivated in different places worldwide. It is one of our best-knownherbs medicinally. It has a good reputation in British herbal encyclopedias memory-enhancing agents. The oil of Sage containscaryophyllene, camphor and borneol (54) etc. The sage provedthe inhibition of acetylcholinesterase action. Furthur researchexhibit that this herb may be useful in the treatment of mild-to-moderate AD.

Salvia rosmarinus Spenn. / Rosemary plant (synonym: Ros-marinus offificinalis L.) in the family Lamiaceae, is an evergreen, perennial shrub growing to a height of 1.5 m. The plant is not frost tender and has the linear leaves about 2–4 cm long, but only 2–5 cm wide. The leaves are green on the top and gray on the bottom. The small flowers are purple, deep blue, pink or white color. Rosemary plant originated in the Mediterranean area. Since ancienttimes, rosemary has been used for improvement and strengtheningof the memory. In ancient Greece, it was considered a mind stimulator. Even at the present date, students in Greece are burning the plant when they are studying for exams. Indeed, it affectsas a stimulator of the blood flflow into the brain and enhancer ofmental alertness.

2.16. Family Magnoliaceae

Magnolia Officinalis Rehder & Wilson / Magnolia tree grows naturally in China typically in mountains and valleys at altitudes of 300–1500 m. It is a deciduous tree growing up to a height of 20 m. The tree has a brown and thick bark, ovate enormous green leaves about 20–40 cm long and 10–20 cm wide, and fragrant creamy-white to butter-yellow large flflowers about 10–14 cm in diameter. The bark of Magnolia offificinalis (Magnoliaceae) is traditionally used in China as a medicine for the memory enhancement and for the treatment of neurosis, anxiety, stroke, dementia etc. Magnolia is able to inhibit scopolamine-induced memory impairment through the inhibition of AChE. The active constituent of Magnolia offificinalis is 4-O-methylhonokiol, honokiol and magnolol (61) (Lee et al., 2011). The polyphenolic compounds 61 and hono-kiol are used in the treatment of fever, headache, neurosis, anxiety and stroke (Woodbury et al., 2013) since ancient times. In vivo experiments showed that honokiol was found to promote the level of acetylcholine in rat hippocampus. Both 61 and honokiol show AChE inhibitory property. The water maze and step-down avoidance tests have shown that Magnolia offificinalis increasing the power of memory and learning skills.

2.17. Family Malvaceae

Theobroma cacao L. / Cacao tree in the family Malvaceae, is asmall evergreen tropical tree, growing to a height of about 8 m. The large leaves about 40 cm long are simple, in alternativearrangement and periodically and replaced by new leaves. Thesmall flflowers are present at all times, however twice a year appearin abundance, their color can be white, yellow, reddish or pink. Flowers are clustered, odourless or foul-smelling and placeddirectly on the trunk and limbs. The fruits are elongated pods invarious color from yellow to deep purple. The ovoid pod is up to35 cm long, about 12 cm wide and contains 20–60 edible seeds,termed as beans. Cacao tree is native to Central and South America. Theobroma cacao contains different types of chemical compoundse.g. alkaloids (theobromine, theophylline and caffeine), glycosides,galactosides, tannins, polyphenols, triglycerides, coumarins, catechins, catechol, linoleic acids, rutin, vitexin etc. All these bringabout its signifificant effect on the enhancement of memory.

2.18. Family Menispermaceae

Tinospora cordifolia (Willd.) Miers / Giloy is a deciduousclimbing shrub. The simple heart-shaped leaves are in alternativearrangement. The species is dioecious, female flowers usually occur solitary, while male flowers are clustered. Red or orangeovoid fruits are clustered. The plant is native to the tropical regions(India, Sri Lanka and Myanmar). This multipurpose herb regenerates brain cells and the whole body. Memory enhancing propertiesof Tinospora cordifolia were observed on the memory and learningskills in normal and memory defificits animals. It increases the synthesis of Acetylcholine. The passive avoidance task and Hebb William maze proved its congnition enhancement property, whenapplied on normal and cognition defificits animals.

2.19. Family Myristicaceae

Myristica fragrans Houtt. / Nutmeg tree is an evergreen treewhich usually grows up to a height of 20 m. The dark green leavesare in alternative arrangement, about 5–15 cm long and 2–7 cmwide. The species is dioecious, the bell-shaped female and maleflflowers are borne on different plants. The female flflowers are insmall groups (1–3 flflowers) and longer than the male flflowers thatare aggregated in larger goups (1–10 flflowers). The fruit, similarin appearance to an apricot is a pendulous drupe with an ediblepulp. Inside the fruit is shiny purple-brown seed about 2 cm long,covered with a red aril. Nugmet tree originated from Banda Islands,Indonesia. The n-hexane extract of M. fragrans seeds in three doses(5, 10 and 20 mg/kg p.o.) was administrated to mice with scopolamine (0.4 mg/kg i.p.) and diazepam (1 mg/kg i.p.) induced memory defificit. The passive-avoidance task and elevated plus-maze testwere used to evaluate learning and memory parameters. A significant improvement in learning skills and memory power was recognized after 3 successive days of M. fragrans extractadministration at a dose of 5 mg/kg p.o. to young and aged mice. Scopolamine and diazepam-induced memory impairment in micewas also reversed with the extract.

2.20. Family Orchidaceae

Gastrodia elata Blume is a perennial herb growing up to a height of 1 m. The unique botanical character of the herb is that the whole plant is chlorophyll-free. Except for fluorescence, the main live-cycle stages of the plant run underground. The vertical, leaflfless stems are yellowish and fringy golden color inflflorescence is about 13–30 cm long. The ovoid rhizome is about 8–12 long. Gastrodia elata is found in North Korea, Siberia, Nepal, Bhutan, India, Japan (Hokkaido, Honshu, Shikoku, Kyushu), Taiwan as well as mainland China. For centuries, the herb is used to treat various disorders including epilepsy, spasm, headache, amnesia, dizziness, stroke, etc. (Chinese Pharmacopoeia Commission, 2015). Rhizoma Gastrodiae (rhizome of G. elata) is the key part of this medicinal plant. Gastrodin (4-hydroxybenzyl alcohol-4-O-b-D-glucopyranoside) is considered as the most important bioactive constituents of Rhizoma Gastrodiae which exhibit high pharmacological intervention. A plethora of research has been investigated for gastrodin (C13H18O7), medicinal importance which has demonstrated remarkable benefificial bioactive activity including memoryimproving, hypnotic, sedative, anti-epileptic, anti-vertigo, preventing osteonecrosis, analgesic, antidepressant, anxiolytic, anti-aging, lowering blood pressure etc. (Zhan et al., 2016). In the light of AD, gastrodin extract or its bioactive constituents has been demonstrated to enhance learning and memory performance in an AD mouse model (Liu and Wang 2012; Hu et al., 2014). In vitro investigation of gastrodin has shown to suppress intracellular and extracellular Ab levels in a dose-dependent manner (Zhu et al., 2014) and further investigation indicated that the cause of this reduction could be associated with the mitigation of b and c-secretase activities (Zhou et al., 2016).

2.21. Family Phyllanthaceae

Phyllanthus Emblica L. / Amla (synonym: Emblica Officinalis Gaertn.) is a tropical deciduous tree that grows up to a height of 18 m. It has green pinnately compound leaves with the greenishyellow flflowers. Edible globular fruits are greenish-yellow color. The tree grows in tropical Southeastern Asia, Southern China, Pakistan, and Bangladesh, particularly in central and southern India, Ceylon, Malaya and the Mascarene Islands. P. emblica contains diverse active constituents like different tannins, vitamin C, oils, polyphenols (gallic acid (75), punigluconin, ellagic acid (73), chebulinic acid, leutolin, apeigenin, quercetin (80), etc.), phyllemblin, amino acids, 3,6-di-O-galloyl-D-glucose, 1-O-galloyl-b-Dglucose, 3-ethylgallic acid (3-ethoxy-4,5-dihydroxybenzoic acid), 1,6-di-O-galloyl b-D-glucose, minerals, flflavonoids (rutin and 80) etc (Variya et al., 2016, Yadav et al., 2017). Presence of vitamin-C, in the amla possesses benefificial calming effects on the memory improvement, cholesterol-lowering property and anticholinesterase activity. Amla shows positive results on memory enhancement in scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) induced memory defificits. It also inhibits AChE activity (Reddy et al., 2010). A study in young and aged rats and mice model showed a dose-dependent improvement in memory scores after administration of Anwalachurna (50, 100, and 200 mg/kg, p. o.) (Parle and Vasudevan, 2007). Numerous studies have shown the neuropharmacological property of P. emblica in the treatment and prevention of dementia which is manifested by the multifunctional characteristic including anti-oxidant property, cholesterol-lowering property, anti-cholinesterase properties, and potency to improve and reverse memory deficits (Ashwlayan and Singh, 2011; Perry and Howes, 2011; Golechha et al., 2012).

2.22. Family Plantaginaceae

Bacopa monnieri (L.) Pennel / Brahmi (also known as water hyssop) is a perennial, non-aromatic herb which grows to a height of 30 cm. The herb is frost tender, has oblong, succulent, thick leaves in alternative arrangement, that are edible. The small, white flflowers have 4–5 petals. Brahmi is native to India and Australia (Aguiar and Borowski, 2013) and also grows throughout the United States and East Asia. Bacopa monnieri (BM) has a long history of use in the AM tradition in the treatment of several ailments, including epilepsy, learning enhancer, lack of concentration, mental illnesses, sedative, stroke, anxiety etc. (Srivastava et al., 2019). All of the herbs investigated for their memory-enhancing properties Brahmi is likely the most studied. The usage of Bacopa monnieri for memory enhancement can be dated back to 800 BCE in India (Rathee et al., 2008). In modern India, Brahmi is used as a tonic for school-going children to improve their mental capacity. The grasp-ing power of the brain and the power to analyze grasped information are also increased by (Singh, 2013). Studies show that the major nootropic bioactive constituents in this herb are alkaloids (such as brahmine, nicotine (62), and herpestine), steroidal saponins (like; D-mannitol and hersaponin, bacopasides I-XII, bacopas-saponins, bacosides A (42) and B, acid A, and monnierin), (Aguiar and Borowski, 2013; Le et al., 2015), which have benefificial influence on enhancement of memory and cognitive function. Bacopa monnieri exhibits neuroprotective, anti-oxidant, and hepatoprotective properties (Rastogi et al., 2012). These bioactive components have promising results in normal rats e.g. learning and memory were facilitated whereas the amnesic effect induced by electroshock, scopolamine, and immobilization stress was inhibited. Furthermore, the activity of protein kinase C (PKC) in hippocamus was enhanced by Brahmi, which contributes to its nootropic action. Bacopa monnieri has also been documented to shown AChE inhibitory activity in patients with AD (Goswami et al., 2011). There have also been preliminary clinical studies suggesting significant improvement of neurocognitive function in humans after treatment with Bacopa monnieri (Peth-Nui et al., 2012; Downey et al., 2013; Neale et al., 2013). Brahmi contributes to soothing and relaxing of the brain cells and restore them to a regular functioning state in adults. Hence, all these fifindings demand to take further research to know the real mechanism of action regulation these pathways/processes.

2.23. Family Rutaceae

Murraya koenigii (L.) Sprengel / Curry tree in the family Rutaceae is an evergreen tree which grows to a height of 6 m. The odd-pinnate leaf usually consists of 11–21 green, ovate, leaflets about2.5–5 cm long that are aromatic. The white, funnel-shaped flowers are small, arranged in clusters and have a sweet fragrance. Fruitsare bluish-black, oblong drupes with a sweet, edible pulp and a single, large, non-edible seed. Curry tree grows in tropical to subtropical regions. This tree is native to Sri Lanka and India. Murrayakoenigii leaves commonly known as ‘curry patta’, are used in Indiandishes as a very common food-additive. Reduction of brain cholinesterase activity as well as cholesterol-lowering effects werereported in diets added with curry leaves that may be attributedto the observed nootropic effect. Therefore, curry leaves can be investigated for use in the management of AD.

2.24. Family Solanaceae

Withania somnifera (L.) Dunal / Ashwagandha is a perennial, evergreen shrub in the family Solanaceae which grows up to a height of 1 m. The species is a hermaphrodite and frost tender. The green leaves are elliptic about 10–12.5 cm long. The small, green followers are bell-shaped. The fruit, enclosed in the calyx is a spherical, orange-red to red berry about 5–8 mm in diameter. It is usually cultivated in the drier regions of India, but found also in Nepal. Withania somnifera belongs to one of the most researched Ayurvedic herbs and its roots are one of the most remarkable ingredients in AM, similar to the status of Ginseng in Chinese therapies. Therefore, it is not surprising that Withania somnifera is often termed as the ‘Indian Ginseng’. The root extract from Ashwagandha (50, 100 and 200 mg/kg; p.o.) in mice led to improvement of retention of a passive avoidance task in a step-down paradigm. Ashwagandha further reversed disruption of acquisition and retention induced by scopolamine (0.3 mg/kg). Moreover, the amnesia produced by acute treatment with electroconvulsive shock (ECS) was attenuated by Ashwagandha immediately after training (Dhulley, 2001).

2.25. Family Theaceae

Camellia sinensis (L.) Kuntze / Green tea plant is an evergreen shrub which grows up to a height of 4 m. The tree has a rough, gray bark and strong taproot. The dark green leaves are oval, in alternative arrangement and about 5–10 cm long. The white flflowers are quite fragrant, solitary or arranged in small groups. The flflower is about 4 cm in diameter with 5–9 petals. Green tea plant is native to South, East and Southeast Asia. However, nowadays, it is cultivated across the subtropical and tropical regions of the world including Japan and Sri Lanka. Camellia sinensis plant produces three types of teas: non-fermented (white and green tea), partially fermented (oolong and red tea) and completely fermented (black tea) (Suzuki et al., 2016; Hayat et al., 2015) and interestingly its bioactive constituents greatly depend on the degree and ease of fermentation process. Tea is globally the second most consumed beverage after the water and its pharmacological properties are extensively documented. It is having potent neuroprotective, free radical scavenging, antioxidative, antioncogenic, hepatoprotective, anti-diabetic, antiviral, and chemopreventive properties because of its diverse chemical constituents including amino acids, aluminum, proteins, phenolic acids (chlorogenic acid, gallic acid (75) or trihydroxybenzoic acid, and caffeic acid), alkaloids (theophylline, caffeine, and theobromine), caffeine, flflavonoids (quercetin (80), kaempferol, and myricetin) and polyphenols (catechins such as epigallocatechin-3-gallate (EGCG, 12), ()-epicatechin gallate (ECG), ()-epicatechin (EC, 49), and (–)-epigallocatechin (EGC)), carbohydrates, minerals, theanine, volatile organic compounds, trace elements, and flfluoride (Mahmood et al., 2010; Legeay et al., 2015) that are benefificial in preventing a plethora of health related ailments including neurodegeneration, hypotension, vomiting, memory loss, skin cancer, lung cancer, and breast cancer, obesity, atherosclerosis, headaches, type 2 diabetes, stomach disorders, gastrointestinal cancer, ovarian cancer, PD, diarrhea, kidney stones (Shivashankara et al., 2014; Yang et al., 2014; Yang and Wang, 2016; Yokogoshi, 2017; Baliga et al., 2018). Since, green tree exhibits a plethora of bioactive molecules especially catechins, it is a well-known source of neuroprotection (Flores et al., 2014; Schimidt et al., 2014; Fernando et al., 2017). It decreases the production of b-amyloid (Ab) monomers, the major cause of AD, which forms proteins that are able to create the amyloid plaques in the brains of patients with AD (Polito et al., 2018). Several recent studies have found that teas (reg and green) as dietary supplements have signifificant potential to reduce/protect memory and learning defificits and hippocampus oxidative stress in an Alzheimer disease model and ischemia–reperfusion (IR) (Martins et al., 2017; Schimidt et al., 2017). The ability of green tea to stop the degeneration in neuronal cells results from the presence of EGCG in the brain, meaning that it can impart its antioxidative effects on the free radicals causing the brain damage. A mouse study in China shows that EGCG from green tea supports the formation of brain cells, which areimportant to memory and spatial learning (Weatherby, 2012). Hence, bioactive teas might be a suitable potent therapeutic candidate against neurodegenerative disorder (Chen et al., 2018) which demands an evaluation of these chemicals in a clinical setting. Furthermore, in clinical studies and various animal models, green tea intake has been shown to reduce cardiovascular disease by reducing total and LDL cholesterol, blood pressure and CVD mortality (Onakpoya et al., 2014; Yarmolinsky et al., 2015; Zhang et al., 2015).

2.26. Family Zingiberaceae

Curcuma longa L. / Turmeric is perennial, tropical, rhizomatous, herbaceous plant, which grows up to a height of 1.5 m. The leaves arise from the pseudostem, which is composed of long, interlocked, succulent leaf petioles. The simple leaves are long and can be simple green color or variegated. The flower spikes arise from the top of the pseudostem. The florets can be white, yellow, orange or pink in color, and the bracts can be also in various colors. The rhizome has a strong orange-yellow color, pepper-like aroma and bitter taste. Turmeric is a traditional Chinese herbal plant and is native to tropical Tamilnadu in Southeast India. Turmeric, obtained from the rhizome of C. longa is known as the golden spice and is widely considered a medicine for the treatment of a plethora of diseases comprising inflammations, arthritic, diabetic wound healing, anorexia, microbial infections, muscular disorders, cancer, hepatic disorders, diabetes, biliary disorders, sinusitis and cough (Li et al., 2012; Kuete, 2017). The rhizomes are the reservoir of diverse compounds out of which curcuminoids (25) (curcumin, 11), principal phenolic compound (Zhao et al., 2012) exhibit multi-function that is potent in the management of various diseases. Additionally, 11 also exhibited several pharmacological properties such as neuroprotective, hepatoprotective, cardiovascular protective, antidiabetic, anticoagulant, anti-inflammatory, antioxidant, antifungal, antiviral, antibacterial, antineoplastic, antifertility and immunostimulant activities in animals (Singh and Sharma, 2011). The pivotal potential of 11 has been well established in treating and preventing neurodegenerative disorders (Kim et al., 2012; Villaflflores et al., 2012). In wistar rats, curcuma oil has been documented to minimize inflflammation of the endothelial cells in postmyocardial ischemia/ reperfusion (Manhas et al., 2014). Curcumin prevents the accumulation of Ab or facilitates its disaggregation at low concentration levels (IC50 = 0.81–1 lM) (Fang et al., 2014). Curcumin has also been shown to protect against Ab neurotoxicity by downregulating Ab synthesis via inhibition of the presenilin 1 (PS1) expression and glycogen synthase kinase-3beta (GSK3b) expression (Caesar et al., 2012; Zhang et al., 2011). In SH-SY5Y neuroblastoma cells treated with 6-hydroxydopamine, 11 has been indicated to arbitrate neuroprotective activity by attenuating quinoprotein development, expression of p-p38 mitogenactivated protein kinases (MAPKs), and activation of caspase-3 (Meesarapee et al., 2014). Curcumin (11) substantially increased cognitive function in a streptozotocin (STZ) model of sporadic AD by restoring downregulated IGF-1 levels (Agrawal et al., 2010). Furthermore, another research found that 11 enhanced the neurotoxicity of 6-hydroxydopamine (6-OHDA) via its anti-inflflammatory action and by restoring the expression of SOD-1 (Tripanichkul and Jaroensuppaperch, 2013). In mice, oral administrated aqueous extract of C. longa led to the inhibition of brain monoamine oxidase-A. 11, as the major bioactive compound from C. longa dis,plays the neuroprotective properties against ethanol-induced brain injury. The 11 enhanced/increased locomotive function in a homocysteine rat model with PD (Mansouri et al., 2012). Concerning epilepsy, in the experimental seizure models, 11 has shown antiepileptic effects (Ahmad, 2013; Peng et al., 2012; Kiasalari et al., 2013) by its antioxidant activity (Choudhary et al., 2013; Noor et al., 2012). Furthermore, 11 is effective in preventing brain injury (cerebral stroke), in addition to antiepileptic effects (Lapchak, 2011; Liu et al., 2013; Yu et al., 2012; Zhao et al., 2010). 11 has boosted candesartan’s neuroprotective activity on brain ischemia via the repression of blood flow and oxidative stress (Awad, 2011). 11 pretreatment decreased infarction and brain lesions, and increased neurological function in rats following Traumatic Brain Injury (TBI) (Samini et al., 2013). In rats experiencing TBI, curcumin derivatives administration enhanced locomotive and cognitive functioning (Wu et al., 2011). Zingiber Officinale Roscoe / Ginger is a perennial, tropical, flowering plant, which grows up to a height of 1.5 m. The leaves are narrow and about 15–30 cm long. They are in alternative arrangement and arise from the pseudostem. Flowering heads are placed on short stems and the herb produces pale yellow, cone-shaped flowers. The rhizomes are irregular in shape with variable colors from light brown to dark yellow. Ginger was cultivated fifirst inSouth Asia, but nowadays is also cultivated in the East Africa andthe Caribbean region. Its rhizomes possess potent memory-enhancing properties. It improves memory power and the wholebody's blood circulation including the supply of nutrients into the brain. Ginger signifificantly improved learning and memory by increasing whole-brain acetylcholinesterase inhibition activity in case of scopolamine-induced memory impairment. It is also reported to inhibit b-amyloid peptide accumulation. Gingerin, gingerol (56), shogaol and zingerone are the major active compoundsin ginger.

3. Use of crude drugs from herbs in memory impairment

Artemisia asiatica Willd. (Asteraceae): a Korean tea plant. Methanolic extract of this plant was administrated to the beta-peptide infused rats. This b-peptide infusion caused toxicity in the PC12 cells in rats. Administration of Artemisia showed a significant result in reversing the toxicity in PC12 cells. A study demonstrated that an alkaloid of Artemisia appeared to be an acetylcholinesterase (AChE) inhibitor with a blocker of bamyloid-induced neurotoxicity causing AD. Celastrus paniculatus Willd. (Celastraceae): the aqueous fraction of C. paniculatus seeds was administrated to rats with sodium nitrite-induced amnesia. The results show an increase in the brain’s acetylcholine (ACh) level by decreasing AChE activity, thus improving memory in amnesic models of mice (Bihaqi et al., 2011). Corydalis ternata (Nakai) Nakai (Papaveraceae): a total methanolic extract of the tuber of Corydalis ternate exhibits considerable inhibition of acetylcholinesterase (AChE). Protopine, an isolated alkaloid from Corydalis showed a dose-dependent inhibitory effect on the acetylcholinesterase activity with IC50 = 50 lM. This inhibitory activity was specifically reversible and competitive in the manner. Foeniculum vulgare Mill. (Apiaceae): a whole plant methanolic extract signifificantly increases latency in step-down avoidance test as well as the inhibition of acetylcholinesterase in mice. Therefore, Foeniculum vulgare can be utilized in the therapy of cognitive disorders e.g. dementia and AD. Gastrodia elata Blume (Orchidaceae): the methanolic extract of the rhizomes of Gastrodia elata in the passive avoidance task results in signifificant prolongation of the shortened step-through latency, induced by scopolamine. Similarly, the n-butanol and ethyl acetate fractions prepared from crude methanolic extract of Gastrodia elata, administered at the dose of 50.0 mg/kg for one week prolonged the scopolamine-induced step-through latency in rats. Moreover, the shortened step-through latency on the passive avoidance task induced by scopolamine was prolonged by gastrodin, as the product isolated from the n-butanol fraction and by p-hydroxybenzyl alcohol, obtained from the ethyl acetate fraction of the methanolic extract. Glycyrrhiza glabra L. (Fabaceae): the aqueous extract of Gly-cyrrhiza glabra was administrated to one-month-old male albino Wistar rats with Diazepam-induced memory impairments. The experiment showed a signifificant increase in learning and memory in the rats and reversed the effect of Diazepam toxicity (Chakravarthi and Avadhani, 2013). Ocimum tenuiflflorum L. (Lamiaceae): a whole-plant aqueous extract of dried Ocimum tenuiflflorum was evaluated on the passive avoidance paradigm and elevated plus-maze in mice. The stepdown latency increasing and the transfer latency decreasing were evident in comparison to control group (treated with piracetam), scopolamine group and age group of mice. The results suggested the possible application of Ocimum tenuiflflorum in the therapy of cognitive disorders (e.g. AD and demetia). Schisandra chinensis (Turcz.) Baill. (Schisandraceae): a deciduous climbing plant, which is native to Northern China and the Far Eastern Russia. The water fraction of this plant at the dose of 25 mg/kg after one-week administration on rats resulted in the prolongation of cycloheximide-induced step-through latency. Interestingly, the water fraction of Schisandra Chinensis seems to be the major active fraction of this plant (Kopustinskiene and Bernatoniene, 2021; Szopa et al., 2017). Scutellaria baicalensis Georgi (Lamiaceae): a flflowering plant native to China, Korea, and Siberia. The extracts of its roots are utilized in the traditional Korean medicine and are benefificial in treatment of the brain diseases. Further, it was reported that the orally administered extracts of this plant improved the memory impairment, which was induced by chronic lipopolysaccharide (LPS) infusion or by chronic cerebral hypoperfusion (Hwang et al., 2011).

4. Effective herbal formulations for memory enhancement

Abana is an Indian Ayurvedic polyherbal formulation, contains16 well-known herbs as composition. It signifificantly reduces theactivity of cholinesterase, which results in to increase in acetylcholine levels in the brain of aged and young mice. The ingredients of Abanaexpress the antioxidant property, which reduces the oxidative stress of the brain cells. Thus, Abana helps to reduce brain impairment and improves neuronal function. The influence of orally administeredAbana on cognitive functions was monitored on groups of agedand young mice. Testing of memory was evaluated by using exteroceptive behavioral models (passive avoidance apparatus and elevated plus-maze test) as well as interoceptive behavioral models(amnesia induced by diazepam, scopolamine and ageing). Abanaimproves the memory score in dose-dependent manner of both aged and young mice. Even, Abana reverses the scopolamine and diazepam-induced amnesia. Therefore, the polyherbal formulation Abana bears promising potential for the treatment of Alzheimer’s disease.

BR-16A (Mentat) is a herbal psychotropic preparation containing various indigenous plant extracts which are well-reputed in theAM. The compositional herbs are: Bacopa monnieri, Acorus calamus,Asparagus racemosus, Evolvulus alsinoides, Withania somnifera, Phyllanthus emblica and Triphala. Mentat on the elevated plus-maze test reduced transfer latency delay induced by scopolamine in mice. Moreover, evaluation of the passive avoidance paradigmrevealed that Mentat also reduces ECS-induced acute and chronicretrograde amnesia in rats. A combination of Mentat and a low dose of aniracetam (a well-known nootropic) in the passive avoidance task brings much better results in the reduction of mistakes. Clinical studies on different age groups with Mentat show improvement in the memory quotient of tested subjects. In normal adults, Mentat attenuates fluctuations of attention and increases memory span. Children with minimal brain damage or behavioral problems improve their ability to learn. Brain-o-brain is a capsule with a unique mixture of herbs likeShankhpushpi, Brahmi, and Sweet flag to improve learning ability, memory power, and naturally, helps to avoid stress and depression. These herbal brain enhancer pills are made especially for all age groups to prevent or decrease forgetting. Indeed, regularly taken

Brain-o-brain is effective to increase gasping power and the natural ability of the brain. This fully natural remedy supports overcoming nervous exhaustion and mental fatigue.

Bramhi ghrita contains four Ayurvedic herbs including Brahmi(Bacopa monnieri) and cowmilk’s ghee. The memory and learningimprovement effect of Brahmi ghrita applied in different doses(30, 50 and 100 mg/kg, p.o.) was tested in rodents. The elevated

plus-maze test was used for the evaluation of memory acquisition and retention in rats. Morris water maze test was used to interpret spatial memory in mice. The elevated plus-maze transfer latency and morris water maze escape latency were signifificantly reduced after administration of Bramhi ghrita (50 and 100 mg/kg, p.o.).

Chyawanprash (Chy) is an Ayurvedic tonic, which contains almost 50 herbs and herbal extracts. One of its basic ingredients is Amla (Phyllanthus emblica) a rich natural source of vitamin C.Consumption of Chy is popular in Indian households. Animal studies confifirmed signifificant inflfluence of Chy in the memory impairment protection effect. Furthermore, administration of Chy (2%w/w) decreases thiobarbituric acid reactive substances (TBARS)in the brain and increases the levels of glutathione. Results indicate a decrease in the free radical generation and an increase in the protection from free radicals. Thus, Chy could be an efficient remedy for the therapy of AD.

Memorie is comprised of 21 kinds of herbal extracts. Theexperimental studies of Memorin were made upon rats using passive avoidance learning paradigm in a shuttle box. Memorin at thedose of 200 mg/kg b.w./day was administered for a fortnight toanimals. Administration of ECS produced signifificant retrograde amnesia in rats. Memory was found to attenuate the ECSinduced amnesia. In clinical studies, when applied to humans, Memory was found to reverse poor memory, age-related dementia, and mental fatigue.

Optimized-Sopung Sunkiwon (OSS) is a polyherbal formulacomprising of six medicinal herbs from SopungSunkiwon. SopungSunkiwon is a traditional medicine that is usually pre-described for people suffering from neurodegenerative disorders. OSS signififi-cantly improves the memory functions via inhibition of AChEactivity. Latency time in the passive avoidance test was signififi-cantly longer for mice treated with OSS compared with controlgroup or group treated with scopolamine. Besides, mice treatedwith OSS exhibited increase of synaptic proteins that facilitateacetylcholine release and synaptic growth (e.g. PSD-95 and synaptophysin). These results show that OSS may act upon memory impairment and increase synaptophysin and PSD-95 in the brain

Shimotsu-to means ‘four substance decoction’. ThisTCM formula consists of the following four crude herbal extracts: Japanese angelica root, peony root, rehmannia root, and cnidium rhizome. Shimotsu-to have benefificial effects on spatial memoryimprovement in rats. Moreover, the study in rat models suggestsimportance of paeoniflflorin (extracted form peony root) andtetramethylpyrazine (extracted from cnidium rhizome) as theenhancers of cognitive functions.

Yukmijihwang-tang derivatives

is a Chinese polyherbal formulation used as memory or cognition enhancer. It consists of six different herbal medicines. Chinese herbal textbook refers toYMJD as an anti-ageing prescription. Besides, it also helps to prevent memory and learning impairment in mice. Studies reportedthat YMJD in stressed rats could increase neurogenesis in the dentate gyrus (hippocampus) along with improvement of cognitivefunctions and memory retention.