Efects of medicinal plants on Alzheimer’s disease and memory def i cits

Muhammad Akram, Allah Nawaz

1 Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences,e University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan

2 First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan

Efects of medicinal plants on Alzheimer’s disease and memory def i cits

Muhammad Akram1,*,#, Allah Nawaz2,#

1 Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences,e University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan

2 First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan

How to cite this article:Akram M, Nawaz A (2017) Ef f ects of medicinal plants on Alzheimer’s disease and memory defcits. Neural Regen Res 12(4):660-670.

Open access statement:Tis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Alzheimer’s disease is an age-related neurodegenerative disorder characterized by memory def i cits. Various studies have been carried out to fi nd therapeutic approaches for Alzheimer’s disease. However, the proper treatment option is still not available.ere is no cure for Alzheimer’s disease, but symptomatic treatment may improve the memory and other dementia related problems. Traditional medicine is practiced worldwide as memory enhancer since ancient times. Natural therapy including herbs and medicinal plants has been used in the treatment of memory def i cits such as dementia, amnesia, as well as Alzheimer’s disease since a long time. Medicinal plants have been used in different systems of medicine, particularly Unani system of medicines and exhibited their powerful roles in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and their efficacy has also been proven in clinical trials. However, the underlying mechanisms of actions are still on the way. In this paper, we have reviewed the role of different medicinal plants that play an important role in the treatment of Alzheimer’s disease and memory def i cits using conventional herbal therapy.

nerve regeneration; memory; Alzheimer’s disease; medicinal plants; efficacy; literature review; neural regeneration

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease affecting older adults. In 1906, Alois Alzheimer, a German neuropathologist and psychiatrist discovered AD. About 24 million World population is suf f ering from dementia, in which majority of patients have AD (Ballard et al., 2011). AD is characterized by memory loss, behavior deterioration, performance impairment, and thought slowness.e condition is mimicked by severe depression (Squire, 1992). Cognitive and neural dysfunction occurs due to accumulation of oxidative damage to nucleic acid, protein and mitochondria in the brain. In Spain, survey was conducted on 1,637 people above 64 years of age regarding subjective memory complaints (SMC). SMC were reported in 524 persons (32.4%). Cognitive performance, mood, sex, education and age are associated with prevalence of SMC. SMC are reported in 24% of people between 65 and 69 years of age. SMC increase 57% in people up to 90 years or above group. SMC are 52.8% in people with anxiety and depression (Montejo et al., 2011). Severe psychological stress or drug use can cause amnesia. Various allopathic medicines are prescribed in AD but they exert side effects. Therefore, herbal medicine could be a good source of drugs for treatment of AD and memory def icit with fewer or no side ef f ects.e present article reviews the medicinal plants that are proven for their efficacy to treat AD and memory def i cits.

Pathogenesis

Two characteristic features are seen in the brain of patients with AD.

1. Senile plaques contain extracellular deposits of amyloid-beta (Aβ), a peptide synthesized by breakage of Aβ precursors (genetic locus 21q21–22). Abnormal deposits of Aβ are also found in blood vessels.

2. Neurofibrillary tangles, dense bundles of abnormal fibers in the cytoplasm of neurons which consist of an altered form of the microtubular-associated protein are found in patients with AD (Hoyer, 1992; Iqbal et al., 2005; Kuljis, 2007; Fernandez et al., 2008; Bamburg and Bloom, 2009).

Molecular Mechanism

The main features of AD are extracellular Aβ pathology and neurofibrillary tau pathology (tangles and threads). For 25 years, most studies have been conducted on the Aβ hypothesis of AD pathogenesis and progression (Pimplikar, 2009). But because of failure in clinical trials of Aβ-targeted treatment and the new concept of prion like propagation of intracellular abnormal proteins, tau has come back into the spotlight as a candidate therapeutic target in management of Alzheimer’s disease. Tau pathologies are found in a range of neurodegenerative disorders, but extensive analyses of pathological tau in diseased brains has indicated that the abnormal tau protein in each disease is structurally distinct(Avila et al., 2004), supporting the concept that progression of the diverse but characteristic tau pathologies occur through prion like seed dependent aggregation. Therefore, intervention in the conversion of normal tau to abnormal forms and in cell-to-cell transmission of tau may be the key for development of disease modifying treatment of AD and other memory def i cits (Hasegawa, 2016).

Drug Targets

Drug Treatment

Probiotics have been reported for their efficacy to enhance memory (Lyte, 2011). Probiotics are used as antidepressant in AD. It reduces anxiety like behavior and attenuates psychological stress. Neurochemicals are produced by microbes. Immunological and neurological effects are induced by probiotics. Probiotics also have immunomodulating activity (Misra and Medhi, 2013). In Chinese and Ayurvedic medicines, medicinal plants are used to treat AD, neurodegenerative changes and cognitive diseases. Various western medicines being used in memory loss are derived from plants. Plant derived alkaloids such as anticholinesterase have been used to treat AD. In the United Kingdom, plant derived galantamine is also used in the treatment of neurodegenerative disorders. Five million Americans are suf f ering from AD and this number will increase up to 7.7 million in 2030. Symptoms of neurodegenerative disorders clearly appear aer 60 years of age (Chengxuan et al., 2009). Etiology of neurodegenerative disorders is linked to genetic defect that is 10–15% of total cases. In AD, loss of neurons appears in subcortical structure, cortex and hippocampus. Various compounds have been identified by phytochemical studies such as alkaloids, sterols, triterpenes, polyphenols, tannins, flavonoids and lignins that have pharmacological activities including anti-cholinesterase and anti-amyloidogenic.

Medicinal plants are playing a significant role in the management of AD and memory deficit. The important traditional therapeutic methods are Ayurvedic, homeopathy, Unani and Sidha systems of medicine. Unani system of medicine offers traditionally a highly scientific health care therapy as a divine giand as a result the global interest of the medical profession is focused on medicinal plants. Traditional system of medicine is fundamentally preventive, protective, nutritive and curative. Therefore, traditional medicines are safe and harmless which treat the patients with fewer or no side ef f ects.

Herbal medicines have their origins in ancient cultures, including those of the Egyptian, Indians and Chinese. It involves the use of medicinal plants to treat AD and enhances general health and well beings. In fact, many pharmaceutical drugs are based on the synthesized adaptations of naturally occurring compounds found in plants. In recent years, interest in herbal medicine has increased, leading to a greater scientific interest in the medicinal use of plants in treating disease and improving health, oen without any signif i cant side ef f ects. Herbal medicines and natural products are the oldest remedies known to mankind. Medicinal plants have been used by all cultures throughout the history. In present scenario, the demand for herbal products is growing, exponentially throughout the World.

In human body, the nervous system coordinates and regulates the various voluntary and involuntary activities of the body. The central nervous system and the autonomic nervous system are interlinked and some drugs affect the CNS producing reactions associated with the autonomic system (McCorry, 2007). Drugs involved with the CNS may have general stimulatory or depressant action with anticonvulsant and psychopharmacological activities. Memory deficit is a major global health problem. Current therapies are inadequate and have numerous adverse ef f ects.ere is an urgent need for possible alternative treatments for AD and memory def i cit. Various medicinal plants are prescribed to enhance the memory. We have reviewed the literature onmedicinal plants used in the treatment of AD and memory def i cit (Xu et al., 2009). Several medicinal plants have been used for decades in different cultures to improve memory such asValeriana of fi cinalis, Punica granatumL.,Salvia offcinalis, Myristica fragrans Bacopa monnieriLinn,Centella asiaticaLinn andEvolvulus alsinoidesLinn. Elufioye et al. (2012) reported some plants used as anti-aging and memory enhancing activities in Sagamu, Nigeria that areBacopa fl oribunda, Angraecum eichlerianum, Parquet inanigrescens, Cleome gynandra, Dalbergia lacteal, Capsicum fructescens, Aframomum melegueta, Digitaria debilis, Musa sapientum, Bryophyllum pinnatum, Abrus precatorius, Ficus exasperate, Dioscorea mangenotiana, Jatropha curcas, Spondia smombin, Capsicum frutescens, Cola acuminate, Mirabilis jalapa, Elaies guineensis, Canna indica, Ipomoea mauritania, Bambusa vulgaris, Cordia millenii, Piper guineense, Dioclea sarmentosa, Cucumeropsis mannii, Eleusine indica, Ocimum basilicum, Khaya ivorensis, Carpolobia alba, Carapa procera, Entandrophragma utile, Xylopiaae thiopica, Garcinia kola, Teobroma cacao, Milicia excels, Blighia sapida, Baphia nitida, Peperomia pellucid, Vernonia amygdalinaandZea mays. Jazayeri et al. (2014) reported some plants having anticholinesterase activity such asBrassica alba, Brassica nigra, Camellia sinensis, Cinchona officinalis, Citrus aurantifolia, Citrus aurantium, Ferula assafoetida, Humulus lupulus, Juglans regia, Juniperus sabina, Myristica fragrans, Pelargonium graveolens, Pistacia vera, Punica granatum, Rheum officinale, Rosa damascena, Salix albaandZizyphus vulgaris. Other plants having memory enhancing properties areJuglans regia(Haider et al., 2011),Cuminum cyminum(Koppula and Choi, 2011),Ficus religiosa(Kaur et al., 2010),Melissa of fi cinalis(Kennedy and Scholey, 2006),Rosmarinus of fi cinalis(Ozarowski et al., 2013),Piper nigrum(Hritcu et al., 2014),Ginkgo biloba(Tan et al., 2015),Bacopa monnieri(Roodenrys et al., 2002),Desmodium gangeticum(Mahajan et al., 2015) andEmblica officinalis Gaerth(Justin Thenmozhi et al., 2016). Herbal medicines have been used to treat various ailments in Unani system of medicine since ancient times. However, there is a lack of scientif i c data on the ef f ectiveness and stability of bioactive chemical constituents in medicinal plants. In this review, we aimed at documenting the information on plants used as a memory enhancer in AD.

Withania somnifera

Withania somniferabelongs to the family Solanaceae. It (500 mg/d) exhibited calming ef f ects on stress and reversed memory loss (Auddy et al., 2008). Cholinergic activity ofWithania somniferahas been reported in a previous study (Schliebs et al., 1997). Memory enhancing activity and cognition improving property ofWithania somniferaincrease due to its ability to increase acetylcholine level in the brain. Neurotic outgrowth activity ofWithania somniferais reported already in human neuroblastoma cells that are time- and dose-dependent.Withania somniferaenhances dendrite and axon regeneration (Tomoharu et al., 2005). A molecular modeling study indicates that withanamides A and C bind to Aβ and inhibit fi bril synthesis (Jayaprakasam et al., 2010).

Curcuma longa

Curcuma longabelongs to the family Zingiberaceae. In Southeast Asian countries, prevalence of AD is low due to consumption of turmeric. It has anti-inf l ammatory activity that is also associated with reduced risk of AD (Aggarwal and Harikumar, 2009).Curcuminreduces the plaque deposition in the brain. Turmeric decreases oxidative stress and amyloid pathology (Mishra and Palanivelu, 2008). In one study, administration of low doses ofcurcuminreduced Aβ level up to 40% in mice with AD as compared to control drug (Shytle et al., 2009).Curcuminat low doses caused 43% decrease in the plaque burden that these Aβ have on the brain of mice with AD (Mishra and Palanivelu, 2008). A previous study indicates that low doses ofcurcuminadministered for long duration are more ef f ective in the treatment of AD as compared to higher doses ofcurcumin(Yang et al. 2005).Curcuminhas an ability to bind with Aβ and inhibits its self assembly (Reinke and Gestwicki, 2007).Curcuminhas powerful anti-inf l ammatory and antioxidant ef f ects (Fan et al., 2015); according to the researchers, these ef f ects help in treating Alzheimer’s symptoms caused by inf l ammation and oxidation (Frautschy and Hu, 2001). Hypercholesterolemia and hyperlipidemia increase amyloid plaques by intracellular accumulation of cholesterol esters (Tokuda et al., 2000). Scientists believe thatcurcuminmight have therapeutic ef f ects on AD by inhibiting cholesterol synthesis and reducing serum peroxides (Soni and Kuttan, 1992).

Convolvulus pluricaulis

Convolvulus pluricaulisbelongs to the family Convolvulaceae. It is used as a memory enhancing agent. A previous study has shown that aqueous and ethyl acetate extract ofConvolvulus pluricaulisincreases memory functions and learning abilities (Bihaqi et al., 2011). In another study, a wide range of secondary metabolites such as steroids, anthocyanins, fl avonol glycosides and triterpenoids have been isolated that are responsible for memory enhancing and nootropic properties (Malik et al., 2011).Convolvulus pluricaulishas been repoted to calm the nerves by regulating the stress hormones synthesis (cortisol and adrenaline) in the body (Sethiya et al., 2009). The ethanolic extract ofConvolvulus pluricaulisand its aqueous and ethyl acetate fractions signif i cantly improved memory retention and learning abilities in rats (Nahata et al., 2008). Another study conducted by Bihaqi et al. (2011) indicated that extracts ofConvolvulus pluricaulisenhance the memory in Wistar rats in a dose-dependent manner. Similarly, administration ofConvolvulus pluricaulisfor 1 week increased memory in aged mice (Sharma et al., 2010). Administration ofConvolvulus pluricaulisincreased the acetylcholinesterase activity in the hippocampal CA1 and CA3 regions associated with the memory function and learning abilities (Dubey et al., 1994).

Centella asiatica

Centella asiaticabelongs to the family Apiaceae. It contains saponins, asiaticosides, madecassoside, madasiatic acid, brahmoside, brahminoside, sasiaticoside, sitosterol, tannins,ascorbic acid, centoic acid, centellic acid, thankuniside, brahmoside, brahminoside, siatic acid, thankuniside, glycoside, triterpine, thankunic acid, vellarin, asiaticosides, thankuniside, and isothankuniside (Siddiqui et al., 2007).Centella asiaticais used in depression, rheumatism, mental weakness, abdominal pain, and epilepsy (Gohil et al., 2010). It is diuretic, anti-spasmodic, anti-convulsive, tonic, stimulant, emmenagogue, antioxidant and spermatogenic (Heidari et al., 2007).Centella asiaticareversed the Aβ pathology and reduced oxidative stress response (Amala et al., 2012).

Rao et al. (2007) reported that treatment withCentella asiatica(Linn) fresh leaf extract enhanced learning ability and memory retention power in Wistar rats. Adult rats of 2.5 months old were selected for this study.ree different doses (2, 4, and 6 mg/kg) of extracts were administered for 2, 4, and 6 weeks. Spatial learning (T-maze) and passive avoidance tests were performed aer the treatment period. Results were compared with those of age matched control rats. Improvement in spatial learning was signif i cant at the dose of 6 mL of extract.e use ofCentella asiaticaextract enhanced memory retention that was evident from passive avoidance test.is data showed thatCentella asiaticaenhances learning ability and memory retention power in adult rats. Veerendra and Gupta (2003) reported efficacy ofCentella asiaticain AD. Its cognition enhancing activities and anti-oxidant ef f ects have been reported. Aqueous extract ofCentella asiatica(100, 200 and 300 mg/kg) was administered for 21 days in streptozotocin (STZ)-induced cognitive impairment and oxidative stress in rats. STZ at 3 mg/kg was intracerebroventricularly injected into male Wistar rats bilaterally on days 1 and 3. Cognitive behavior was assessed aer 13, 14 and 21 days of treatment. Rats were sacrif i ced for assessment of oxidative stress aer 21 days of treatment. Cognitive behaviors of rats treated withCentella asiaticaextract improved signif icantly.e maximum response was observed aer administration of extract at the doses of 200 and 300 mg/kg. Results from Veerendra and Gupta (2003) showed thatCentella asiaticais ef f ective in STZ-induced cognitive impairment in rats.

Celastrus paniculatus

Celastrus paniculatusbelongs to the family Celastraceae. It prevented neuronal cell damage against hydrogen peroxide toxicity due to its antioxidant activity (Godkar et al., 2006). Administration ofCelastrus paniculatusprevents neuronal cell damage caused by glutamine induced toxicity (Godkar et al., 2003).Celastrus paniculatusincreases cholinergic activity that contributes its ability to improving memory performance (Bhanumathy et al., 2010). Aqueous extract ofCelastrus paniculatushas antioxidant and cognition enhancing properties (Kumar and Gupta, 2002).Celastrus paniculatusextracts protected neuronal cells against hydrogen peroxide induced toxicity in part by virtue of their antioxidant and free radical scavenging activities (Katekhaye et al., 2011).

Nardostachys jatamansi

Nardostachys jatamansibelongs to the family Caprifoliaceae. It contains sesquiterpene valeranone that has been used for treatment of stress (Lyle et al., 2009). In a study,Nardostachys jatamansiexhibited memory retention and learning enhancing abilities in aged and young mice and reversed scopolamine and diazepam induced amnesia.Nardostachys jatamansialso reversed aging induced amnesia (Joshi and Parle, 2006). Karkada et al. (2012) reported efficacy ofNardostachys jatamansiin the prevention of stress induced memory def i cit.

Coriandrum sativum

Coriandrum sativumbelongs to the family Apiaceae. In one study,Coriandrum sativumwas given for 45 days for its effi cacy on cognitive function in male Wistar rats.is study was conducted in comparison with aging, scopolamine and diazepam induced amnesia.Coriandrum sativumexhibited memory enhancing effects due to its antioxidant, anti-inflammatory and cholesterol lowering activities (Vasudevan and Milind, 2009).

Ficus carica

Ficus caricabelongs to the family Moraceae. It was investigated for its effect in retrieval, retention and acquisition of spatial recognition.Ficus caricacontains quercetin that plays an important role in memory def i cit and AD due to its antioxidant activity. For this study, mice with memory def i cit and normal mice were used. Rectangular maze model and Y-maze were used to assess efficacy ofFicus caricaon cognitive functions. Hexane extract (100 and 200 mg/kg) was administered to adult swiss Wistar albino mice. In this study, Bacopa monniera and scopolamine were used as standard drug and amnestic agent respectively.Ficus carica200 mg/kg exhibited maximum nootropic response that is near to response exhibited by a standard drug Bacopa monniera. In conclusion,Ficus caricaat lower doses exhibits mild memory enhancing ef f et and higher doses evoke better learning ability and alter behavior (Saxena et al., 2013).

Ginkgo biloba

Ginkgo bilobabelongs to the family Ginkgoaceae. It contains bilobalide that has a neuroprotective activity (Chandrasekaran et al., 2001).Ginkgo bilobadecreases free radical and improves memory in patients with AD (Shi et al., 2010). It contains flavonoids that are involved in memory enhancement (Bastianetto et al., 2000). Gingko biloba prevents neurodegeneration and GABA inhibitory neurotransmission induced by hippocampal corticosterone (Walesiuk and Braszko, 2009). Administration ofGinkgo bilobasignif i cantly improved memory and learning performance in albino rats (Nalini et al., 1992).

Ilex paraguariensis

Ilex paraguariensisbelongs to the family Aquifoliaceae. It has a memory enhancing property. It contains vitamin B12, B1 and C.Ilex paraguariensisis being used as an anti-dementia agent (Bastos et al. 2007). Its memory enhancing property was investigated in different rat models (Colpo et al., 2007).Ilex paraguariensishas been shown to improve short and long term memory (Rui et al., 2008).ere is evidence thatIlex paraguariensisfor treatment of vascular dementia improves memory (Heck et al., 2007). Literature review indicates thatIlex paraguariensisis ef f ective in the treatment of neurodegenerative disorders such as AD (Muzzafera, 1997).

Commiphora whighitti

Commiphora whighittibelongs to the family Burseraceae. It is a potent cognition enhancer for memory improvement in scopolamine induced memory def i cits (Gujran et al., 2007). Another study shows that brain pathology develops in cholesterol fed rabbits similar to AD (Ghribi, 2008), which is supported by clinical trials in human, showing that statin treatment decreases the risk of AD (Raja and Hoyer, 2004). Memory enhancing and anti-dementia activity ofCommiphora whighittihas been reported that is due to reduction in acetylcholinesterase contents in the hippocampus (Lannert and Hoyer, 1998).

Glycyrrhiza glabra

Glycyrrhiza glabrabelongs to the family Fabaceae. It contains pentanol, hexanol, linalool oxide, tetramethyl pyrazine, terpinen, terpinol, geraniol, propionic acid, benzoic acid, ethyl linolenate, methyl ethyl ketone, butanediol, feuferaldehyde, furfuryl formate, trimethylpyrazine, maltol, glycyrrhizin, tannin, and glycyrrhizic acid (Rekha and Parvathi, 2012).Glycyrrhiza glabrais used in gastric ulcer, lung congestion, hoarseness and throat problems (Dastagir and Rizvi, 2016). Memory enhancing activity ofGlycyrrhiza glabrawas reported in scopolamine induced dementia (Ambawade et al., 1998). Dhingra et al. (2004) reported the memory enhancing activity ofGlycyrrhiza glabrain mice.ree dose levels (75, 150, 300 mg/kg, p.o.) ofGlycyrrhiza glabraextracts were administered to mice in 7 successive days.Glycyrrhiza glabraat 150 mg/kg was found ef f ective in memory enhancement.

Lepidium meyenii

Lepidium meyeniibelongs to family Brassicaceae. It is known as Maca which shows improvement in learning abilities and memory function (Julio et al., 2007).Lepidium meyeniiexhibited memory enhancing activity in patients with AD. It enhances memory by increasing level of acetylcholine (Wang et al., 2006). It improves experimental memory impairment induced by ovariectomy, due in part to its acetylcholinesterase inhibitory and antioxidant effects. Results showed thatLepidium meyeniican enhance memory retention and learning abilities in ovariectomized mice and this activity might be related, at least in part, to its ability to decrease lipid peroxidation and acetylcholinesterase in ovariectomized mice (Rubio et al., 2011).

Panax ginseng

Panax ginsengbelongs to the family Araliaceae. A previous study has shown that learning ability increases in animals by consumptions ofPanax ginseng. Recent studies have shown the efficacy ofPanax ginsengpowder, extract and various ginsedosides on AD usingin vivoandin vitromodels (Heo et al., 2008; Cho, 2012; Hee et al. 2013). Patients receiving Korean white ginseng powder (4.5 g/d) or Korean red ginseng powder (9 g/d) showed significant improvement in Clinical Dementia Rating, Mini-Mental State Examination scores and the Alzheimer’s Disease Assessment Scale aer 12 weeks of ginseng treatment in comparison with those in the control group (Heo et al., 2008; Lee et al., 2008).

Emblica officinalis

Emblica officinalisbelongs to the family Euphorbiaceae. It exhibited significant improvement in memory retention of young and aged rats in a dose-dependent manner. It reversed the diazepam and scopolamine induced amnesia. As a memory enhancer and reversal of memory def i cits,Emblica of ficinalisplays an important role in the treatment of memory def i cits and AD (Mani et al., 2007). A study was conducted to investigate the memory enhancing effect of piracetam when used together withEmblica officinalisandcurcuma longaagainst aluminium-induced cognitive dysfunction and oxidative damage in rats. Aluminium chloride at 100 mg/kg was given orally to rats for 6 weeks.Emblica officinalis(100 mg/kg, p.o.),curcumin(100 mg/kg, p.o.) and piracetam (200 mg/kg, i.p.) were concomitantly administered to rats daily for 6 weeks. Elevated plus maze task paradigms and Morris water maze tests were used to evaluate memory on days 21 and 42 of treatment. On day 43 of treatment, rats were sacrif i ced to evaluate the extent of oxidative stress. Oxidative stress was signif i cantly reduced and memory was signif i cantly improved in rats treated withEmblica officinalis(100 mg/kg, p.o.),curcumin(100 mg/kg, p.o.) and piracetam (200 mg/kg, i.p.) than the rats treated only with piracetam (200 mg/kg, i.p.). As antioxidant and memory enhancer agent,Emblica of fi cinaliscould be used to treat memory loss and AD (Ramachandran et al., 2013).

Magnolia officinalis

Magnolia officinalisbelongs to the family Magnoliaceae. It improves the scopolamine induced memory def i cits (Lee et al., 2009).Magnolia of fi cinalisinhibits acetyl cholinesterase activity (Jae et al., 2009). Ethanolic extract ofMagnolia of fi cinaliscontaining honokiol and magnolol has been reported to possess antioxidant ef f ects (Lo et al., 1994; Chiu et al., 1997; Kong et al., 2000).In vitroantioxidant activities of various Soxhlet and supercritical fl uid extracts have been reported, with the ethyl acetate Soxhlet extract being the most active (Li and Weng, 2005). Biphenolic lignins (magnolol (29) and honokiol (28) derived fromMagnolia of fi cinalis, have the ability to enhance the choline acetyltransferase ef f ects and inhibit the acetylcholine cleavage and have also been shown to release acetylcholine from the hippocampus (Hou et al., 2000). Both compounds exhibitedin vivoantioxidant ef f ects (Lo et al., 1994). Magnolol showedin vitroneuroprotective activity (Lee et al., 2000).e compound also exhibited anti-inf l ammatory ef f ectin vivoandin vitro(Wang et al., 1992, 1995). Honokiol exhibits anti-inflammatory activity by inhibiting reactive oxygen species synthesis (Dikalov et al., 2008). Asan anti-inf l ammatory and antioxidant agent,Magnolia of fi cinalisplays an important role in the management of AD and memory def i cits (Jie et al., 2000; Chen et al., 2001; Liou et al., 2003).

Zingiber officinale

Zingiber of fi cinalebelongs to the family Zingiberaccae. It is used for treatment of headache, rheumatism and stomach trouble (Malhotra and Singh, 2003). It improves memory impairment induced by scopolamineviainhibition of acetylcholinesterase activity (Hanumanthacar et al., 2006). As a booster of antioxidant and a reducer of free radical,Zingiber officinaleplays an important role in the treatment of AD and memory def i cits (Masuda et al., 1997). In another study, male rats (250–300 g) were divided into treatment and control groups. The treatment group was further divided into three subgroups. Plant mixed in food at a ratio of 6.25% was administered in the fi rst group. Plant extract at 50 mg/kg and 100 mg/kg (intraperitoneal) was administered to the second and third subgroups, respectively. Shuttle box test and Y maze test were used to investigate acquisition-recalling and spatial recognition behaviors. Significant improving effects on recall, retention and acquisition were observed in male rats aer intraperitoneal and oral administration ofZingiber of fi cinale(Gharibi et al., 2013).

Tinospora cordifolia

Tinospora cordifoliabelongs to the family Menispermaceae. Pharmacological activities include anti-fertility, antioxidant and immunomodulating activities (Reddy and Rajasekhar, 2015).Tinospora cordifoliapossesses a memory improving ef f ect in animals with memory def i cits (Malve et al., 2014). The mechanism by whichTinospora cordifoliaimproves memory is the synthesis of acetylcholine and immunostimulation (Asuthosh et al., 2000). Administration ofTinospora cordifoliaincreases the cognitive function in patients with AD (Lannert and Hoyer, 1998).

Punica granatum

Punica granatumbelongs to the family Punicaceae. It contains corilagin, granatin, punicacortein A, pedunculagin and punicafolin.Punica granatumis used in diarrhea and dysentery (Das et al., 1999). It is anthelmintic and astringent. Cambay et al. (2011) reported the ef ficacy ofPunica granatumflower in learning and memory performance impaired by diabetes mellitus in rats. In this study, rats were divided into fi ve groups (n= 12): control, streptozocin, streptozocin + pomegranate fl owers at 300, 400 and 500 mg/kg/d. Results showed that rats in the streptozocin group showed memory impairment than those in the control group. Administration of pomegranate fl ower powder led to improvement in learning abilities and memory retention in diabetic rats. Pomegranate fl ower powder supplementation decreased oxidative stress and alleviated learning and memory impairment as compared to streptozocin induced diabetic rats.erefore,Punica granatumfl ower plays an important role in the treatment of neurological def i cits in patients with diabetes mellitus.

Crocus sativus

Crocus sativusbelongs to the family Iridaceae. There is an increasing trend to prescribe theCrocus sativusin the treatment of AD and memory def i cits. In clinical trials, ef ficacy ofCrocus sativuswas investigated in 54 patients aged 55 years during a 22-week study period. Patients were randomly assigned to receive donepezil 10 mg/d or capsule saf f ron 30 mg/d.Crocus sativusat 30 mg/d was found to be ef f ective similar to donezepil in patients with mild to moderate AD after 22 weeks of treatment. Adverse effects occurred at similar frequencies between donezepil-treated and saffron-treated patients, with the exception of vomiting which occurred more in donezepil-treated patients (Akhondzadeh et al., 2010). Another similar study was conducted to investigate the ef f ects of saf f ron extractversusmemantine in decreasing cognitive deterioration of patients with moderate to severe AD. In this clinical trial, 68 patients received saffron extract (30 mg/d) or memantine (20 mg/d) for 1 year. Functional Assessment Staging and Severe Cognitive Impairment Rating Scale were used to evaluate patients every month and possible adverse effects were recorded.Crocus sativusat 30 mg/d was found to be ef f ective similar to memantine in patients with moderate to severe AD after 1 year of treatment.ere was no signif i cant difference in frequency of adverse effects in both treatment groups (Farokhnia et al., 2014).

Cissampelos pareira

Cissampelos pareirabelongs to the family Menispermaceae. It was investigated for its ef f ect on memory and learning in mice. Memory and learning was testedviapassive avoidance paradigm and elevated plus maze. Hydroalcoholic extract ofCissampelos pareirawas given orally at 100, 200 and 400 mg/kg for 7 days. Memory and learning significantly improved aer administration ofCissampelos pareiraat 400 mg/kg in mice.Cissampelos pareiraextract at 400 mg/kg reversed the scopolamine induced amnesia. Nootropic ef f ect ofCissampelos pareirawas observed that may be due to decreased activity of acetylcholinesterase enzyme and increased antioxidant and anti-inf l ammatory activities (Pramodinee et al., 2011).

Mellisa officinalis

Mellisa of fi cinalisbelongs to the family Lamiaceae. It is anxiolytic, anti-inf l ammatory and antidepressant (Taiwo et al., 2012). In a randomized clinical trial conducted by Kennedy et al. (2002), 20 young participants received a single dose of 300, 600 and 900 mg ofMellisa of fi cinalisor a matching placebo at 7 day intervals.Mellisa of fi cinalisat 600 mg significantly improved memory and cognitive performance. Akhondzadeh et al. (2003a) conducted a study to investigate the efficacy and safety ofMellisa of fi cinalis(60 drops/day) in the treatment of AD. Patients were randomly divided into test and placebo groups.Mellisa officinalisextract was administered to patients between 65 and 80 years of age for 4 months. At 4 months of treatment,Mellisa of fi cinalisextract exhibited a signif i cant ef f ect on cognitive function as com-pared to the placebo group. There were no significant side ef f ects observed in both treatment groups except agitation in the placebo group.

Moringa oleifera

Moringa oleiferabelongs to the family Moringaceae.Moringa oleiferaleaf extract contains Vitamin C and E that are anti-oxidant and are involved in enhancing memory in AD (Pakade et al., 2013). It has nootropics activity and combat stress in AD (Mohan et al., 2005).Moringa oleiferaalters monoamines that are involved in memory process (Ganguly and Guha, 2008). A study conducted in rats indicated thatMoringa oleiferaameliorates the colchicines-induced AD by modifying levels of monoamines such as nor epinephrine, dopamine and serotonin (Obulesu and Rao, 2011).

Salvia officinalis

Salvia of fi cinalisbelongs to the family Lamiaceae. It enhances memory retention by interacting with muscarinic and cholinergic pathways that are involved in memory retention process (Eidi et al., 2006). A study was conducted to investigate the efficacy ofSalvia of fi cinalisin 42 patients (18 female and 24 male, age between 65 and 80 years) with AD living in Tehran, Iran. Aer 4 months of treatment, signi fi cant effi cacy was observed inSalvia o ffi cinalistreated patients than in the placebo-treated patients. The findings indicate the e ff ectiveness ofSalvia o ffi cinalisin the treatment of AD and memory de fi cits (Akhondzadeh et al., 2003b).

Myristica fragrans

Myristica fragransbelongs to the family Myristicaceae. It contains camphene, b-pinene, sabinene, cymene, garaniol, d-borneol, linolool, terpineol, safrol, elemicin, myristicins, phenylpropane derivatives, lauric acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, oleic acid and b-sitosterol (Maeda et al., 2008).Myristica fragransis used in nervous disorders, digestive disorders, leukemia, bodyache, vomiting, tachycardia, dizziness and memory disturbances (Asgarpanah and Kazemivash, 2012). It is hypolipidemic, antidepressant, antioxidant and antibacterial (Narasimhan and Dhake, 2006). N-hexane extract ofMyristica fragransat three dose levels (5, 10 and 20 mg/kg p.o.) was administered orally to young and aged mice for 3 successive days.is drug was found ef f ective at 5 mg/kg in reversing scopolamine and diazepam induced impairment in learning and memory.is study validated use ofMyristica fragransin the management of AD and memory def i cits (Parle et al., 2004).

Bacopa monnieri

Bacopa monnieribelongs to family Scrophulariaceae. It contains sterols, saponins, alkaloids, monnierin, hersaponin acid A, herpestine and brahmine (Singh, 2012). Traditional healers useBacopa monnieriin combination with Centella astiatica and Evolulus alsinoides to treat memory disorders and AD (Russo and Borrelli, 2005).Bacopa monnierienhances memory in patients with AD. It is adaptogenic, neuroprotective, antimicrobial and memory enhancer (Aguiar and Borowski, 2013). Carlo et al. (2008) reported the efficacy ofBacopa monnierion cognitive performance, anxiety, and depression in the elderly and found ef f ective in enhancing cognitive functions in the elderly.is study justif i es its use as a memory enhancer. Another study demonstrated thatBacopa monnieriinhibits cholinergic degeneration and exhibits cognition enhancing activity in a rat model of AD (Uabundit et al., 2010).

Evolvulus alsinoides

Evolvulus alsinoidesbelongs to the family Convolvulaceae. Nahata et al. (2010) reported the efficacy ofEvolvulus alsinoidesin learning behavior and memory enhancement activity in rodents. Ethanol extracts ofEvolvulus alsinoidesand its ethyl acetate and aqueous fractions were investigated for memory enhancing activities in rats. Extracts at 100 mg/kg and 200 mg/kg were administered orally. All extracts signif icantly enhanced learning ability and memory retention in rats. Furthermore, these extracts (0.3 mg/kg, i.p) signif i cantly reversed scopolamine induced amnesia in rats. Nootropic activity of extracts was compared with piracetam as the standard drug. Extract showed significant memory enhancing activity in the step-down and shuttle-box avoidance paradigms.

Ficus racemosa

Ficus racemosabelongs to the family Moraceae. Faiyaz et al. (2011) reported the memory enhancing activity ofFicus racemosabark in rats and found thatFicus racemosa(250 and 500 mg/kg) signif i cantly increased acetylcholine level in the hippocampus of rats.is study suggests its potential to treat memory def i cits in patients with AD.

Ginkgo ginseng

Ginkgo ginsengbelongs to the family Ginkgoaceae. Wesnes et al. (2000) reported the memory enhancing ef f ect ofGinkgo ginsengin 256 healthy middle-aged volunteers through a 14-week study period. A questionnaire including sleep, mood, and quality of life was fi lled before and during the treatment period. Assessment was done at weeks 0, 4, 8, and 14 of the treatment.Ginkgo ginsengpowder was found ef f ective in improving memory def i cits.

Conclusion

In this paper, we have reviewed more detail about the management of AD and the medicinal plants with potential therapeutic values. Despite the bulk of knowledge regarding this complex disease, there is no complete cure except symptomatic treatment. So, the herbal therapy is now anticipated to control AD progression and help to relieve the symptoms related to AD. Herbal therapy can improve the life quality of patients with AD and memory deficits. Worldwide research is being done to find effective treatment of AD. This review reveals that herbal therapy is an encouraging choice as alternative to treat AD. Medicinal plants used in different systems of medicine particularlyUnani system of medicines exhibit their powerful role in the management and cure of memory disorders. Most of herbs and plants have been chemically evaluated and some of them are in the clinical trial stage.e results are magnif i cent and considerable. However, the underlying mechanisms of action are still on the way. As reviewed in this paper, future clinical trials involving larger sample sizes are needed to investigate the role of different medicinal plants and the underlying mechanisms.

Author contributions:MA conceived and designed the work and wrote the paper. AN performed the analysis with constructive discussion and revised the paper. Both authors approved the fnal version of this paper.

Conficts of interest:None declared.

Plagiarism check:This paper was screened twice using CrossCheck to verify originality before publication.

Peer review:Tis paper was double-blinded and stringently reviewed by international expert reviewers.

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Copyedited by Li CH, Song LP, Zhao M

*< class="emphasis_italic">Correspondence to: Muhammad Akram, M.D., Ph.D., makram_0451@yahoo.com; makram_0451@hotmail.com.

Muhammad Akram, M.D., Ph.D., makram_0451@yahoo.com; makram_0451@hotmail.com.

#Tese authors contributed equally to this study.

orcid: 0000-0001-7863-8803 (Muhammad Akram)

10.4103/1673-5374.205108

Accepted: 2017-03-29