ABSTRACT
Alzheimer’s disease (AD), the most common type of dementia, is a progressive neuro-degenerative disease severely affecting memory and cognitive function. It causes linguistic and visuo-spatial deficiencies, and behavioral problems like indifference, aggressiveness and depression as disease progresses advanced stages. No cure is available for Alzheimer’s, though symptomatic treatment improves memory and other symptoms. Natural products ease the symptoms of many kinds of diseases and offer a treatment option for many diseases at least successfully slowing the progress. Medicinal plants and plant products have been historically employed to improve brain function and treat memory disorders like amnesia, dementia. Though, various studies have described the utility of plants for treatment of Alzheimer’s, but with limited scientific evidence. Though, it has been reported that early start of utilization memory enhancing agents and brain tonics can be beneficial in AD. The present review is to summaries the herbal medicines which have reported to have some kind of CNS activity and may be utilized for slowing progression, symptomatic treatment and research in the treatment of Alzheimer’s disease (AD) and its related symptoms.
ALZHEIMER’S DISEASE
Alzheimer’s disease (AD) is a most severe type of neurodegenerative disease affecting brain, the symptoms of this disease become more severe and worsens with time.1 The disease is named after Alois Alzheimer, a German physician, who reported reported the first case of “Presenile Dementia”.2 He studied the brain of the patient and found the diffused cortical atrophy and particular changes in cortical cell clusters, plaques and tangles of nerve fibers which are identified as beta amyloid plaques and neuro-fibrillary tangles of tau in 1980.3,4 In 1984 the clinical diagnostic criteria for AD was revised for mild-cognitive impairment and dementia stages of AD and established the role of biomarkers.5–6
The Alzheimer’s patients are unable to notice the changes in the brain even for years till they experience noticeable symptoms like linguistic issues and memory loss. The AD remains undetected even after 20 years or more of actual start of condition. The symptoms are visible due to the significant damage to the neurons in brain associated with thinking, learning and memory beyond repair.7 As the disease progresses, it starts affecting neurons in other parts of the brain thus affecting capability to carry out day to day functions like swallowing, walking and sitting straight to name some. Patients become bed ridden and depends on others for basic chore needing 24×7 attentions making him very week ultimately resulting in demise.8 The differences in normal brain and brain of AD patients is given in Table 1.
| Normal Human brain | Alzheimer brain |
|---|---|
| The healthy human brain consists of billions of healthy neurons | The Alzheimer brain consists of injured and dead/dying neurons throughout the brain |
| Connections between neurons networks are strong | Connections between neurons networks are generally broken down |
| Continuous communication between neurons of different parts of the brain, and from the brain to the muscles and organs of the body takes place. | Communication process among neurons is disturbed with loss of function resulting in cell death. |
| Very good capacity to transmit information via electrical and chemical signals. | Capacity to transmit information via electrical and chemical signals is substantially lost. |
| In healthy aging though the brain shrinks to some extent but, neurons are not lost in large numbers. | In Alzheimer disease brain regions begin to shrink with loss of neurons |
| At the microscopic level, the Alzheimer’s brain shows amyloid plaques outside the neurons and neurofibrillary tangles inside the neurons. |
Difference between Alzheimer’s disease and Dementia.
AD and dementia are erroneously considered same. AD is the most common cause/form of dementia. Dementia is characterized by difficulty with memory, speech/language, intellectual and thinking skills which affect patient’s ability to do normal day-to-day activities due to changes in the brain of the person with AD.9–10 The AD and dementia is differentiated in Table 2.
| Alzheimer’s Disease | Dementia |
|---|---|
| Alzheimer’s disease is a most common type of dementia. But not every dementia is Alzheimer’s. | Dementia describes difficulty in memory that affects, daily activities, and communication abilities. |
| Deposition of unusual proteins in the brain causes AD. | Dementia can be caused by many conditions and degenerative diseases |
| Formation of protein plaques and tangle in the brain disturbs communication within brain. | Different set of brain cells or different part of brain is damaged in different type of dementia. |
| Slowly the cells damaged and no longer can function properly. | |
| AD is a progressive disease of brain, slowly worsening with time, impairing memory and cognitive functions. | It mostly affects people in the older age. Persons above 85 years generally have some kind of dementia. The cases are relatively low in young person |
| Though many theories exist, the exact cause is unknown and cure is not available for AD. | |
| Early signs and symptoms ofAD include: Disorientation | Early signs and symptoms of dementia include: Symptoms of psychosis, depression, anxiety and distress |
| It is irreversible | It can be reversible |
Epidemiology
As per WHO, worldwide, more than 55 million people worldwide are living with dementia and nearly 10 million new cases are reported every year.11It is reported that an estimated 0.7% of the global population (51.6 million people) has dementia and the number is projected to reach 152 million by mid-century. It is the seventh leading cause of death among all diseases.
Almost 30% increase in reported AD cases every five year is observed as per the report of the World Health Organization (WHO). Prevalence, incidence, mortality, and disability adjusted life a years (DALYs) due to AD has drastically increased worldwide.5,12,13 Projections indicate that AD related deaths will increase from the current 2.4 million/year to 5.8 million/year by 2040.
The age is an important prevalence factor as AD has a progressive increase proportional to aging. 14 About 5% of individuals over 65 years and 20% of those over 80 years suffer from AD, indicating that the prevalence rate doubles every 5 years.15 According to Javed et al. the high-income regions like Western Europe show higher prevalence than Asia and Africa.16,17
The available and reported data can be misleading as it is from health records. In many developing countries not all the health problems especially related to dementia in older people are reported. To get maximum correct data there is a need for improvement in the search and registration of the data for unregistered or under-diagnosed AD patients.18
The AD not only is a burden for quality of life and social issues but also a very big financial issue. According to the World Alzheimer Report 2015, the overall costs for the care of AD were 818 billion dollars, an increase of 35.4% compared to 2009. The trend suggests that the cost may be rising to 2 trillion in 2030. 19
PATHOPHYSIOLOGY OF ALZHEIMER’S DISEASE
Alzheimer’s disease is attributed to many aspects like the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/ mitochondrial dysfunctions.20Patients show loss of neurons and temporo-frontal cortex atrophy causing the deposits of amyloid plaques and inflammation. The prominent features of AD is presence of an irregular cluster of protein fragments and tangled fiber bundles. It increases the monocytes and macrophages in cerebral cortex and microglial cells in the parenchyma.21
AD causes neuronal losses in the entorhinal cortex, amygdala, and hippocampus. The cortical association of the frontal, temporal, parietal cortices and sub-cortical nuclei and the cholinergic basal nucleus also suffer neuronal loss. The deposited tangles show a specific pattern which starts from the trans-entorhinal cortex and continuing to the entorhinal cortex, the CA1 region of the hippocampus and then to cortical association area where frontal, parietal and temporal lobes join. The severity of dementia depends more on tangle formation than numbers of amyloid plaques.22The cognitive decline and brain atrophy, including hippocampal atrophy growthis linked with growth of hyper-phosphorylated tau proteins and amyloid β deposition. 23AD patients also show high levels of redox transition metals in the brain 24 and reduced cholinergic receptor binding in specific brain regions which may be related to neuropsychiatric symptoms.25
SYMPTOMS OF ALZHEIMER’S DISEASE
Alzheimer’s disease is basically identified by the symptoms before clinical diagnosis. The symptoms of Alzheimer’s disease start showing very mild symptoms initially like partial memory loss and progress to very severe dementia and other behavioral changes. The symptomatic disease is being recognized and confirmed pathologically, clinically and epidemiologically. 26–29
The different symptoms of AD are summarized in Table 3.
| Cognitive Symptoms | Non-cognitive symptoms | Symptoms affecting normal living |
|---|---|---|
| Memory loss | Depression | Occasional muscle twitches. |
| Language difficulties | Hallucinations | Groaning, moaning, or grunting. |
| Executive dysfunction indicating loss of advanced planning and intellectual skills. | Delusions | Increased sleeping. |
| Repeating questions | Agitation | Loss of bowel and bladder control. |
| Getting lost | Aggression | Difficulties with performing daily activities. |
| Shortened attention span | Restlessness | Difficulty swallowing and eating unaided |
| Losing things often | Anxiety | Difficulty in dressing. |
| Seizures | Difficulty in driving. | |
| Tearfulness | Difficulty in shopping, counting money and paying bills. | |
| Impulsive behavior |
CAUSES OF ALZHEIMER’S
There is still no confirmatory and confidant causes of AD. Studies have identified and linked some risk factors of AD which include progressive age, low physical and cognitive activity, head injury, depression, hypertension, family history, apolipoprotein (Apo) E4 status and other such comorbidities.30
The main histopathological features of Alzheimer’s disease are neuritic/senile plaques indicated by phosphorylated TAU and neuro-fibrillary tangles showing deposits of amyloid. These features are associated with the severity of the dementia. Synaptic density in AD is a measure of neuronal loss.31–36Various risk factors for AD are given in Table 4.
| Social and demographic factors | Medical history and medicines | Family history and genetic factors | Lifestyle related factors |
|---|---|---|---|
| Progressive age Racialand ethnic profile National profile | Head injuries Oestrogen replacement Hypertension Diabetes Homocysteine and cholesterol level Depression Herpes simplex (mediatedby thepresence of ApoEe4. | Family history: AD in degree relative increases the risk.Conditions that mutate chromosomes 1, 14, and 21.Genotype ApoEDown’s syndrome:Longer and higher education and intelligence are protective against AD. | Heavy Drinking Smoking Diet Occupational and recreation factors Alcohol |
Management of AD
Currently a multi-factorial personalized management of AD is attempted consisting of following components:
Communication
A sincere and honest communication between patient, physician and caregiver generally results in identification and confirmation of symptoms, proper diagnosis and evaluation of AD and suitable strategy and treatment plan. Open communication amongst these three is a key to a successful treatment and management of AD.
Caregiver support
Care and support is very important in management of AD. Training and educating them for future risks and conditions arising from worsening of AD and how to deal with them can result in better management and control. Knowing beforehand and being prepared for effects dementia related to AD on cognition, normal function and behavior, expectations. Understanding which situations can worsen the symptoms or pose dangers for safety and well-being may result in good care and management.37
Behavioral approaches
Strategies such as normal and cool interactions, easy language with simple words, engaging in pleasurable activities restricting only when situation may pose danger and safety is concerned38 make them feel better and helps in management. Having consistent and normal simple surroundings, planned routines and prompt medical decisions can help immensely involving regular physical activity also has beneficial effects on symptoms and control of AD.39
Sleep
Disturbance in sleep is one major cause of AD. Sleep patterns directly or indirectly affect AD. Improper sleep accumulates Amyloid-β (Aβ) triggering the decline in memory and progressing to AD. Proper and sufficient sleep is as central for managing and treating AD, providing anticipatory and therapeutic benefits.
Other options for improving symptoms of AD include cognitive behavioral therapy, light therapy, music therapy exercise etc depending on patient situation and disease severity.40
Medical Approach
Along with behavioral and lifestyle changes treatment with prescription drugs under medical supervision is recommended and needed. FDA-approved AD medications like Acetyl choline esterase inhibitors (AChEI) e.g. donepezil, galantamine, rivastigmine, and the NMDA(N-methyl-D-aspartate) antagonist e.g. memantine are the only FDA-approved drugs for AD medications.41 Only these four drugs are currently approved by USFDA and available for the treatment of AD-associated dementia. But as per the reports their utility is very limited.
Most commonly used acetyl cholinesterase inhibitors (AChEI0drugs acts on central nervous systems (CNS) cholinergic pathways. Galantamine, a natural alkaloid, acts as an allosteric modulator at nicotinic acetylcholine receptors thus benefiting in alleviating symptoms of AD. These drugs are approved for mild to severe dementia and are often used to treat patients in earlier pre-dementia stages showing progressive memory impairment established on cognitive testing results.42
Recently excessive glutamate saturation at excitatory synapses caused by decreased glutamate reuptake from microglia has been identified as one of the patho-physiological mechanism of AD. To target this Memantine is the first approved AD acting on N-methyl-d-aspartate (NMDA) receptor and glutaminergic pathways. Memantine is prescribed in combination with stable ChEI therapy for improved safety profile in patients with AD.43
Challenges in Alzheimer Therapy
The progression of AD spans from asymptomatic to severely impaired conditions. Identifying these conditions is challenging as the separation between symptoms of normal aging and preclinical AD is not clearly defined. The reasons for relatively higher incidence of AD in women are also not yet properly understood.44 Future research may be able answer many questions about AD in future.
Use of NSAIDs reduce the risk of developing AD indicating inflammation can be a relevant target in AD. But conclusive outcomes have not yet been generated.45 It may be due to action of anti-inflammatory drugs on generic targets and not on specific neuro-inflammatory components of AD. Control and treatment of inflammation at early stages of AD is necessary to study the effectiveness of targeting inflammation in neuro-degeneration.46
Greater knowledge of the complex features of AD such as behavioral, mood, metabolic disturbances and inflammation may develop successful innovative therapies.47 Promising new therapies with immune-globulins and monoclonal antibodies are currently under evaluation. Earlier Intervention with re-purposed drugs, combination therapy, anti-inflammatory agents or drugs that can modify underlying conditions could prove beneficial in successful outcomes in AD therapy.48
Herbal Approach for Alzheimer’s Disease
There is a pressing need for the alternative treatments for AD with minimal or no side effects as current AD therapies are inadequate and have many adverse effects. Herbal medicines are considered as very safe and affordable, having potential clinical efficacy, and drug-drug synergistic interactions.49 In Ayurveda and Chinese traditional medicines several drugs are given for treatments of various diseases. Numerous scientific studies have reported the important role of medicinal plants in the treatment of nervous disorders, enhancement of the memory and improvement of nervous system in general. Herbal therapy for AD promises to have more advantages as compared to existing drug therapies having unavoidable side effects thus improving the patients’ quality of life.50
Herbal medicines are of interest in many diseases, especially in psychiatric and neurological disorders as dissatisfaction of patients with current treatment, to have control over their healthcare decision, and herbal medicine is in accordance with their beliefs and values. Several studies and documents indicate an exceptional role of herbal medicines in the treatment of AD.51
The phyto-chemical analysis of herbal drugs used for treating AD reveals the presence of compounds like tannins, lignans, poly-phenols, flavonoids, sterols, triterpenes and alkaloids indicating anti-amyloidogenic, anti-inflammatory, anti-cholinesterase, hypo-lipidemic, and antioxidant effects as possible mechanisms of action.52
Limitations of Herbal Drugs
For AD, the herbal drugs should target multiple mechanisms like Aβ production, fibrillation, Aβ-mediated oxidative stress, and neuro-inflammation. There are some limitations of herbal drugs like hepatic and other toxicity if used in higher concentration, lack of statistically significant clinical efficacy poor ability to cross BBB. Processing limitations like difficulty in obtaining the active compounds in large quantities, effect of irregular environmental conditions on the activity of herbal drugs and preparations without stringent adherence to GMP guidelines.51
Herbal Drugs for the Treatment of AD
Herbal plants according to many researchers have been proved effective on Alzheimer disease and dementia. The herbal drugs mainly decrease the symptoms and progress of disease without or with very few side effects. Table 5 give information of medicinal plants that are used or have potential for the treatment of AD.53,54
| Sl.No | Plant name | Family | Part used | Chemical constituents | References |
|---|---|---|---|---|---|
| 1. | Melissa officinalis | Lamiaceae or Labiatae | Leaf | Rhamnocitrin Luteolin, Flavonoids (quercitrin) Protocatechuic acid Triterpenes (ursolic and oleanolic acids)Polyphenolic compounds, Monoterpenoid aldehyde Rosmarinic acid Caffeic acid Monoterpene glycosides Rannins Sesquiterpenes Citral essential oils | 54 |
| 2. | Salvia officinalis | Lamiaceae or Labiatae | Flowers, leaves, and stem | Alkaloids Flavonoids Tannins Glycosidic derivatives e.g., cardiac glycosides, flavonoid glycosides Saponins, Phenolic compounds e.g., coumarins Terpenes/terpenoids e.g., monoterpenoids, diterpenoids, triterpenoids Poly acetylenes Steroids Carbohydrate Fatty acids | 55 |
| 3. | Centella asiatica | Apiceae | Fresh root | Aciaticosides (sapanonins) | 56 |
| 4. | Cantharantus roseus | Apocynaceae | Dried root | Vincristine Vinblastine | 57 |
| 5. | Ginkgo biloba | Gincoknaceae | Dried Leaves | Ginkolides A,B,C,J and M | 58 |
| 6. | Abutilon indicum Linn. | Malvaceae | Whole | Alkaloid Saponins Flavonoids Glycosides steroids Amino acid. | 59 |
| 7. | Acanthus ebracteatus Vahl. | Acanthaceae | Aerial Part | Alkaloids Flavonoids, Triterpenoids Steroids Saponins | 60 |
| 8. | Aegle marmelos Linn. | Rutaceae | Fruit Pulp | Marmelosin, Luvangetin Aurapten Psoralen Marmelide Tannin. | 59 |
| 9 | Albizia procera (Roxb.) Benth | Fabaceae | Bark | Triterpenoids, Glycosides Phytosterols Saponins, Tannins Phenolic compounds, Flavonoids Carbohydrates. | 61 |
| 10 | Bacopa monniera Linn. | Scrophulariaceae | whole | Bacosides A and B Bacopasides III to V Bacosaponins A, B,and C, Bisdesmosides Bacopasaponins D, E, and F, Jujubogenin Betulic acid Sterols Alkaloids polyphenols Sulfhydryl compounds | 61 |
| 11 | Buxus sempervirens Linn. | Buxaceae | Wood ad leaves | Aalkaloids namely Buxine, Parabuxine, Parabuxonidine Butyraceous Volatile oil. | 61 |
| 12 | Butea superba Roxb. | Fabaceae, | Roots | Flavonoids Flavonoid glycosides Sterol compounds Βsitosterol Campesterol Stigmasterol. | 62 |
| 13 | Carthamus tinctorius Linn | Asteraceae. | Flower | Phenolics Flavonoids, Alkaloids Steroids Quinochalcone C-glycosides, Quinone-containing chalcones Oils Proteins Lignans, Minerals, Carboxylic acids Polysaccharides. | 61 |
| 14 | Cassia fistula Linn. | Legmues | Root | Anthraquinones derivatives, Tannins, Oxyanthra-quinones, Oxalic Acids. | 61 |
| 15 | Nelumbo nucifera Gaertn. Stamen | Nelumbonaceae | Stamen | Megastigmanes, Nelumnucifoside, Sesquiterpene, Nelumnucifoside B Alkaloids Flavonoids. | 61 |
| 16 | Rhododendron luteum Sweet | Ericaceae, | Whole | Luteum was found to be a-cadinol δ-cadinene A-terpineol Benzyl salicylate A-muurolene and 1,6-germacradien-5β-ol | 62 |
| 17 | Withania somnifera (L.) | solanaceae | Roots | Withasomidienone, Withanolides A to Y, Withaferin A, Withasomniferin A, Withasomniferols A to C, Dehydro withanolide R, Withanone, Alkaloids, Sitoindosides VII to X, Phytosterols Beta-sitosterol, Amino acids High amounts of iron. | 63 |
| 18 | Aegle marmelo | Rutaceae | Leaves and fruit | Coumarin, Xanthotoxol, Imperatorin Aegeline, and Marmeline | 64 |
| 19 | Nigella sativa | Ranunculaceae | Fruit | Fixed oil Proteins Alkaloid Saponin Essential oil | 65 |
| 20 | Piper retrofractum Vahl. | Piperaceae | Leaves | Amides Alkaloids phenylpropanoids, Alkyl glycosides, Lignans | 66 |
| 21 | Acorus calamus | Acoraceae | Root or rhizomes | α-Asarone β-asarone | 67 |
| 22 | Blumea balsamifera DC | Asteraceae | Leaves and whole plant | BlumpenesA, B, C, andD | 68 |
| 23 | Cannabis sativa | Cannabaceae | Flowers and fruits | Tetrahydrocannabinol | 69 |
| 24 | Citrus grandis Osbek | Rutaceae | Leaves,pulp and peel | 3,5,6,7,8,3′,4′-Heptamethoxyflavone | 63 |
| 25 | Clerodendrum infortunatum L. | Verbenaceae | Aerial parts | Sterols, sugars Flavonoids Saponins Acteoside | 63 |
| 26 | Lygodium flexuosum (L.)Sws. | Lygodiaceae | Leaves, stem and root | Alkaloids Flavanoids, Saponins and Cumarins | 70 |
| 27 | Rosmarinus officinalis | (Lamiaceae) | Leaves | phenolic compounds, di- and triterpenes Essential oils | 71 |
| 28 | Areca catechu L. | Arecaceae | Fruit | Alkaloids, Flavonoids, Tannins, Triterpenes, Fatty acids, | 71 |
| 29 | Ipomoea aquatica | Convolvulace | Leaves | Alkaloids Steroids, Saponin, Phenols, Reducing sugar, Flavonoids, Tannins | 70 |
| 30 | Caesalpinia crista L. | Leguminosae | Fruit and seeds | Alkaloids Cassane-diterpenes, Flavonoids, nor-cassane diterpenes, Proteins Saponins Triterpenoids | 70 |
| 31 | Senna tora Roxb. | Leguminosae | Leaves | Alkaloids, Glycosides Tannins volatile oils Minerals Vitamins | 70 |
| 32 | Phyllanthus reticulatus | Phyllanthaceae | Root and leaves | Tannic acid, Terpenoids Flavonoids phenolic compounds Steroids as main chemical constituents | 70 |
| 33 | Convolvulus pluricaulis | Convolvulaceae | Whole plant, Leaves, stem and root | Alkaloids, Glycosides, Flavonoids, Carbohydrates Proteins Sterols Gum Mucilages compounds | 58 |
| 34 | Smilax zeylanica L. | Smilacceaae | Leaves and roots | Daucosterin Daucosterol Caffeic acid Catechin Engeletin Friedelin Epicatechin Heloniosides Hydroxyflavan Piceid Isoengeletin Naringenin Quercetin Flavonoids Resveratrol Resin Rutin Trihydroxystibene Scirpusin Saponin Stilbenes Smilacin Seiboldogenin Taxifoli Smilasides Tannin Vanillic acid | 71 |
| 35 | Abrus precatorius L. | Fabaceae | Leaves | Abrusogenin, Saturated monoglyceride Unsaturated triglyceride | 72 |
| 36 | Aframomum melegueta K. Schum | Zingiberaceae | Seeds | Mrytenyl acetate Isolimonene γ-elemene | 73 |
| 37 | Albizia adianthifolia(Schumach.) W.F. Wigh | Fabaceae | Leaves | Apo-carotenoids, Dipeptide Steroids Elliptosides Flavonoids Histamines, Triterpenoids Imidazolyl carboxylic acids, Triterpene Saponins Essential oils Fatty acids | 74 |
| 38 | Allium cepa L. | Liliaceae | Bulb | Phenolic acids Thiosulfinates Flavonoids. | 75 |
| 39 | Angraecum eichlerianus Bory. | Orchidaceae | Leaves | Isovaleraldoxime | 76 |
| 40 | Bacopa floribunda(R.Br) Wettst. | Scrophuliaceae | Leaves | Bacosidesand bacopasaponins, are triterpene saponins of the dammarane class, which contain 2 or 3 sugars each. | 77 |
| 41 | Baphia nitida Lodd. | Papilinionaceae | Leaves and bark | Tannins, Flavonoids and saponin glycosides | 78 |
| 42 | Bombax buonopozenseP. Beauv | Bombacaceae | Leaves | Tannin, Alkaloids, Saponin, Cyanogenic glycosides, Steroids, Flavonoids and Phenols. | 79 |
| 43 | Digitaria horizontalisWilld. | Poaceae | Whole plant | Avena fatua crabgrass (Digitaria sanguinalis | 80 |
| 44 | Elaeis guineensis Jacq. | Arecaceae | Leaves | Fatty acids Carotenes Vtamin E | 81 |
| 45 | Flueggea virosa (Roxb. ex Willd | Phyllantaceae | Leaves and root | Alkaloids Triterpenoids Resins Steroids Cardiac glycosides Bergenin Menisdaurin Anthraquinones. | 82 |
| 46 | Jatropha curcas L. | Euphorbiaceae | Fruits | Saponins Steroids Tannins Glycosides Alkaloids Flavonoids | 83 |
| 47 | Justicia schimperi(Hochst.) Dandy | Acanthaceae | Leave and root | Alkaloids Lignans Flavonoids Terpenoids Iridods Diterpenoids Triterpenoids | 84 |
| 48 | Musa paradisiacal L. | Musaceae | Leaves | Nor-epinephrine Serotonin Indole compounds Tryptophan Tannin Albuminoids Crystallisable and non-crystallisable sugars Vitamin C&B Fats Mineral salts | 85 |
| 49 | Musa sapientum L. | Musaceae | Fruits | Sitoindoside-I-IV Acyl steryl glycosides Steryl glycosides Sitosterol myo-inositylβ-D-glucoside Sitosterol gentiobioside | 86 |
| 50 | Olax subscorpioidea Oliv. | Olacaceae | Stem and bark | Alkaloids Saponins Tannins Cardiac glycosides Terpenoids Phenols | 87 |
| 51 | Piper guineense Schum. And Thonn | Piperaceae | Leaves and fruits | Alkaloid Cyanogenic glycosides Tannin Flavonoid Anthraquinones Saponin Phenol | 88 |
| 52 | Rauvolfia vomitoria Afze. | Apocynaceae | Root | Deserpidine Ajmalicine Ajmaline | 87 |
| 53 | Rinorea dentata Kuntze | Violaceae | Leaves | Saponins Tannins Steroids Cardiac glycosides Flavonoids Alkaloids Terpenoids Phenols, Carbohydrates | 89 |
| 54 | Spondias mombin L. | Anacardiaceae | Leaves | Saponins Alkaloids Flavonoids Tannins Oxalates Phytates Cyanogenic glycosides | 90 |
| 55 | Talinum triangulare (Jacq.) Willd | Portulaceae | Leaves | Hydroxycinnamates Benzoic acid derivatives Alkaloids Flavonoids Carotenoids Phytosterols Glycosides Terpenes Saponins Allicins Lignans | 91 |
| 56 | Piper spp. | Piperaceae | Leaves | Phenolic glycosides Flavanol glycosides. | 92 |
| 57 | Curcuma longa | Zingiberaceae | Rhizomes | ar-turmerone, β-sesquiphellandrene Curcumenol | 93 |
| 58 | Tinospora cordifolia (Giloy) | Menispermaceae | Root | Diterpenoid lactones Glycosides Steroids Sesquiterpe-noid Phenolics Aliphatic compounds Essential oils Fattyacids Polysaccharide | 94 |
| 59 | Magnolia officinalis | Magnoliaceae | Bark | Magnoloside Ia,Ib Ic Magnoloside IIa , IIb Magnoloside IIIa Magnoloside IVa Magnoloside Va Crassifolioside Phenylethanoid glycosides | 95 |
| 60 | Lepidium meyenii | Brassicaceae | Root | Aromatic glucosinolates Benzyl glucosinolate(glucotropaeolin) M-methoxybenzyl glucosinolate(glucolimnanthin) | 96 |
| 61 | Glycyrrhiza glabra | Fabaceae | Root | Glycyrrhizin Rhamnoliquirilin Liquirtin Liquiritigenin Glucoliquiritin Apioside Licoarylcoumarin Licopyranocoumarin Flavonoids Prenyllicoflavone A 1-metho-Xyphaseolin Shinflavanone Shinpterocarpin Glisoflavone Coumarin-GU-12 Saponins | 97 |
| 62 | Huperzine A | Lycopodiaceae | Moss | Alkaloids Huperzine A | 98 |
Phytochemicals for treating AD
Many researchers not only reported the herbal plants but also evaluated active constituents from these plants for their effectiveness against AD. Table 6 depicts information related to phyto-constituents isolated and identified for their effectiveness for treating AD with proposed mechanism of actions for each constituent.
| Sl. No. | Chemical Constituents | Application | References |
|---|---|---|---|
| 1 | Withanamides(Withania somnifera) | Enhanced dendrite and axon regeneration. Scavenges unobstructed radicals Obstructs activated neuronal cell death by amyloid plaques.Protects PC-12 cells from β-amyloid | 99-100 |
| 2 | Convolvine(Convolvulus pluricaulis) | Enhanced acetylcholinesterase activity in the hippocampal CA1 and CA3. Affecting memory and learning abilities | 101 |
| 3 | Celapanin, Celapagine and Celapanigine(Celastrus paniculatus) | Increased cholinergic activity contributing to improved memory | 102 |
| 4 | Bilobalide(Gingko biloba) | Averts neuro-degeneration and GABA inhibition by hippocampal corticosterone | 103 |
| 5 | Quercetin, and guggulsterones E and Z(Commiphora whighitti) | Reduced acetylcholinesterase in the hippocampus | 104 |
| 6 | Macamide (Lepidium meyenii) | Enhanced memory due to increased acetylcholine level | 105 |
| 7 | Rosmarinic acid and ellagic acid (Salvia officinalis) | Memory retention is increased due to interactions with muscarinic and cholinergic pathways. | 106 |
| 8 | Rutin, quercetin, rhamnetin, kaempferol, apigenin, and myricetin (Moringa oleifera) | Increased levels of monoamines (nor epinephrine, dopamine and serotonin) | 107 |
| 9 | Bebeerine (Cissampelos pareira) | Decreased activity of acetylcholinesterase Increased antioxidant and anti-inflammatory activities | 108 |
| 10 | Brahmine and bacosides (Bacopa monnieri) | Decreses activity of divalent metals, ROS, peroxides formation, and lipoxygenase movement. | 109 |
| 11 | Flavonols and phenolic compounds (Ficus racemosa and Ficus carica) | Increased levels of Acetylcholine in the hippocampus. | 110 |
| 12 | Baicalein(Scutellaria baicalensis) | Show powerful anti-BACE1 activity [IC50 =μM]Cause Aβ-oligomerization with fibrillation and inhibition of Aβ-induced toxicity in PC12 cells Disaggregation of preformed Aβ amyloid fibrils. | 111 |
| 13 | Myricetin (Myrica rubra) or hydroxyquercetin (Oryza sativa) | Enhance the crossing of BBB Neuro-protective against neuronal cell injury by Aβ. | 112,113 |
| 14 | Berberine (Coptis chinensis) | Regulate βAPP processing Decreases Aβ protein Mitigates lack of BACE1 protein levels. | 114 |
| 15 | Epiberberine and Groenlandicine(Coptidis Rhizoma) | Inhibit BACE1 activity | 115 |
| 16 | 2,2,4-Trihydroxychalcone acid (TDC)(Glycyrrhiza glabra) | Decreases BACE1 activity Reduced Aβ40 and Aβ42 stages in the HEK293 Overcomes the BACE1 activity on the βAPP by reducing -APPswe cells. | 116 |
| 17 | Rutin (Fagopyrum esculentum) and Galangin (Alpinia officinarum) | βAPP selective BACE1 inhibitors. unstabilize BACE1 division. | 117 |
| 18 | Asperterpenes A and B meroterpenoids(Aspergillus terreus) | Prevents BACE1 Lowers Aβ42 development | 118 |
| 19 | Ferulic acid (Oryza sativa and Triticum aestivum) | Reduce the Aβ groups and BACE1 enzymatic action and affects BACE1 stability. It also affects mRNA expression level. | 119 |
| 20 | Cardamonin (Boesenbergia rotunda) | Shows potent inhibition and does not alter the TACE(α-secretase). | 120 |
| 21 | Salvianolic acid (Salvia miltiorrhiza) | Disaggregate Aβ fibril formation. Modulates BACE1 activity and decreases Aβ production. | 121 |
| 22 | Medium-chain fatty acids (MCFAs) with medium-chain triglycerides. (Coconut oil) | Inhibits Aβ by Suppressing ADP-ribosylation factor 1 | 122,123 |
Clinical trial on Alzheimer diseases based on herbal drugs
Phase II and III clinical trials of Ginkgo biloba extract (GBE) to investigate its efficacy in the treatment of AD were conducted in 2016. The studies showed promising results indicating changes in the MMSE, ADAS-cog electroencephalography P300, and 1.5 T MRI. GBE also improved daily activities, renal function, liver function, neuropsychiatric state and reduced depression.124,125
Phase III clinical trials were conducted to find out the effectiveness of coconut oil in AD with mild to moderate symptoms. It was reported that coconut oil due to presence of medium-chain fatty acids and medium-chain triglycerides shows remarkable improvement in AD.126,127
A double blind, randomized and placebo-controlled trial to evaluate efficacy of Salvia officinalis extract was carried out in 2003. Outcome was measured by ADAS-cog CDR-SB (Alzheimer’s disease assessment scale).128 Similar study for Melissa officinalis extract was also reported. The results show significant therapeutic effects in treating AD in both drugs and remarkable decrease in episodes of agitation in AD patients in case of Melissa officinalis was observed.129
The traditional Chinese medicine Yi-Gan San was evaluated in randomized, controlled trial for treating behavioral and psychological symptoms along with effects on quality of life of patients suffering from dementia. The outcomes were measured by NPI Barthel Index MMSE (mini-mental state examination scale; NPI, neuropsychiatric).130 Also a randomized, double-blind, placebo-controlled study for ‘Ba Wei Huang Wan’, a Chinese herbal medicine has been conducted. Both the studies indicated improvements in patients with more than 12 months of AD diagnosis.131
CONCLUSION
The review discusses basic pathophysiology and epidemiology of AD including risk factors and management. There are very few options of medical intervention and need for the search of new drugs for treating AD. This can be achieved by exploring herbal options. Herbal medicines are generally considered as safe with fewer side effects. A large number of plants show neuronal activities and can be exploited for treating AD. The plants and their phytoconstituents mentioned in this review can be used not only for improvement of Alzheimer memory loss but also treating various other disorders. The scientific community should be actively involved in identifying the plants, along with their mechanism of action so that it can be used for safe and better treatment for AD. Research on these herbal and other Ayurvedic medicine may provide new functional leads and effective alternatives for treating AD.
References
- Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, et al. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: A cross-sectional and longitudinal cohort study. Lancet Neurol. 2020;19(6):513-21. [CrossRef] | [Google Scholar]
- Mohamed T, Shakeri A, Rao PPN. Amyloid cascade in Alzheimer’s disease: recent advances in medicinal chemistry. Eur J Med Chem. 2016;113:258-72. [CrossRef] | [Google Scholar]
- Chase TN, Farlow MR, Clarence-Smith K. Donepezil plus solifenacin (CPC–201) treatment for Alzheimer’s disease. Neurotherapeutics. 2017;14(2):405-16. [CrossRef] | [Google Scholar]
- Kim DH, Lee SB, Young LD, VYang HD. Hist Alzheimers Dis Dem Neurocognitive Disord. 10.3390/geriatrics6010005. 2016;15(4):115-21. [CrossRef] | [Google Scholar]
- Soria Lopez JA, Gonzalez HM, Leger GC. Chapter 13. Alzheimer’s disease. In: Handbook of clinical neurology. 2019;167:231-55. [CrossRef] | [Google Scholar]
- Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120(3):885-90. [CrossRef] | [Google Scholar]
- Barthelemy N, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med. 2020;26:398-407. [CrossRef] | [Google Scholar]
- Available from: [cited 22.11.2022]. [CrossRef] | [Google Scholar]
- Brahma D. The persistence of memory: the burden of Alzheimer’s disease in India. (Online article) [cited Jul 1, 2021]. Available from: https://www.brookings.edu/blog /upfront/2019/09/20/the-persistence-of-memory-theburden-of-alzheimers-disease-in-india/
[CrossRef] | [Google Scholar] - WHO https:. Available from: http://www.who.int/news-room/fact-sheets/detail/dementia
[CrossRef] | [Google Scholar] - Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s disease: Past, present, and future. J Int Neuropsychol Soc. 2017;23(9-10) 81831 https: [CrossRef] | [Google Scholar]
- Alzheimer report. 2015 http://alz.co.uk/research/worldreport-2015 (World Accessed May 02, 2016) [CrossRef] | [Google Scholar]
- Wimo A, Guerchet M, Ali G, Wu Y, Prina AM. World alzheimer report. Alzheimer’s and Dementia. 2017;13(1):1-7. [CrossRef] | [Google Scholar]
- Manual diagnostico e Estatistico de transtornos mentais-DMS-5. 5rd Artmed, editor. Porto Alegre, 2014. Available from:. [CrossRef] | [Google Scholar]
- Javed SF, Giebel C, Khan MA, Hashim MJ. Epidemiology of Alzhemiers disease and other dementia:rising global burden and forecasted trends F1000Research; 2021.10.25. [CrossRef] | [Google Scholar]
- Weiner MW, Friedl KE, Pacifico A, Chapman JC, Jaffee MS, Little DM, et al. Psychological stress-induced immune response and risk of Alzheimer’s disease in veterans from Operation Enduring Freedom and operation Iraqi freedom. Clin Ther. 2020;42(6):974-82. [CrossRef] | [Google Scholar]
- Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: A brief overview. J Head Trauma Rehabil. 2006;21(5):375-8. [CrossRef] | [Google Scholar]
- Thunnan DJ, Branche CM, Sniezek JE. The Epidemiology of Sports-Related Traumatic Brain Injuries in the United States: Recent Developments. J Head Trauma Rehabil. 1998;13(2):1-8. [CrossRef] | [Google Scholar]
- Alzheimer [cited May 02, 2016] Available from: . [CrossRef] | [Google Scholar]
- Available from: [cited 22.11.2022]. [CrossRef] | [Google Scholar]
- Herrera E, Caramelli P, Silveira ASB, Nitrini R. Epidemiologic Survey of Dementia in a Community-Dwelling Brazilian Population. Alzheimer Dis Assoc Disord. 2002;16(2):103-8. [CrossRef] | [Google Scholar]
- Blennow K. Biomarkers in Alzheimer’s disease drug development. Nat Med. 2010;16(11):1218-22. [CrossRef] | [Google Scholar]
- Prakash A, Dhaliwal GK, Kumar P, Majeed ABA. Brain biometals and Alzheimer’s disease – boon or bane?. Int J Neurosci. 2017;127(2):99-108. [CrossRef] | [Google Scholar]
- Feldman H, Woodward M. The staging and assessment of moderate to severe Alzheimer disease. Neurology. 2005;65:10-7. [CrossRef] | [Google Scholar]
- Brayne C. Elephant in the room—healthy brains in later life, epidemiology and public health. Nat Rev Neurosci. 2007;8:233-9. [CrossRef] | [Google Scholar]
- Nestor PJ, Scheltens P, Hodges JR. Advances in the earlydetection of Alzheimer’s disease. Nat Rev Neurosci. 2004;5:34-41. [CrossRef] | [Google Scholar]
- Chong MS, Sahadevan S. An evidence-based clinical approach to the diagnosis of dementia. Ann Acad Med Singapore. 2003;32:740-8. [CrossRef] | [Google Scholar]
- Spaan PE, Raaijmakers JG, Jonker C. Alzheimers’s disease versus normal ageing: a review of the efficiency of clinical and experimental memory measures. J Clin Exp Neuropsychol. 2003;25:216-33. [CrossRef] | [Google Scholar]
- McGirr S, Venegas C, Swaminathan A. Alzheimer’s disease: A brief review. J Exp Neurol. 2020;1(3):89-98. [CrossRef] | [Google Scholar]
- Leroi I, Lyketsos C. Neuropsychiatric aspects ofdementia BurnsA. 2005:55-64. [CrossRef] | [Google Scholar]
- McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939-44. [PubMed] | [CrossRef] | [Google Scholar]
- Burns A, Byrne J, Ballard C, Holmes C. Sensory stimulation in dementia: an effective option for managing behavioural problems. BMJ (compact Ed.). 2002;325(7376):1312-3. [CrossRef] | [Google Scholar]
- Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: Diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology. 1993;43(2):250-60. [PubMed] | [CrossRef] | [Google Scholar]
- Atri A. Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019;39(2):227-40. [CrossRef] | [Google Scholar]
- Kishita N, Backhouse T, Mioshi E. Nonpharmacological interventions to improve depression, anxiety, and quality of life (QoL) in people with dementia: an overview of systematic reviews. J Geriatr Psychiatry Neurol. 2020;33(1):28-41. [CrossRef] | [Google Scholar]
- Heinrich M, Lee Teoh H. Galanthamine from snowdrop–the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol. 2004;92(2-3):47-62. [PubMed] | [CrossRef] | [Google Scholar]
- Olazarán J, Reisberg B, Clare L, Cruz I, Peña-Casanova J. Nonpharmacological therapies in Alzheimer’s disease: a systematic review of efficacy. Dement Geriatr Cogn Disord. 2010;30(2):161-78. [PubMed] | [CrossRef] | [Google Scholar]
- Ballard C, Khan Z, Clack H, Corbett A. Nonpharmacological treatment of Alzheimer disease. Can J Psychiatry. 2011;56(10):589-95. [PubMed] | [CrossRef] | [Google Scholar]
- van Someren EJW, Mirmiran M, Swaab DF. Non–pharmacological treatment of sleep and wake disturbances in aging and Alzheimer’s disease: chronobiological perspectives. Behav Brain Res. 1993;57(2):235-53. [PubMed] | [CrossRef] | [Google Scholar]
- Christensen A, Pike CJ. Menopause, obesity and inflammation: Interactive risk factors for Alzheimer’s disease. Front Aging Neurosci. 2015;7:130 [PubMed] | [CrossRef] | [Google Scholar]
- Mosconi L, Berti V, Quinn C, McHugh P, Petrongolo G. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLOS ONE. 2017a;12(10):e0185926 [PubMed] | [CrossRef] | [Google Scholar]
- Liu F, Day M, Muñiz LC, Bitran D, Arias R. Activation of estrogen receptor-b regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci. 2008;11(3):334-43. [PubMed] | [CrossRef] | [Google Scholar]
- Brinton R. D. Array. Array. Array;Array:Array-Array. [CrossRef] | [Google Scholar]
- Akhondzadeh S, Noroozian M. Alzheimer’s disease: Pathophysiology and pharmacotherapy. IDrugs. 2002;4:1167-72. [CrossRef] | [Google Scholar]
- Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology. 2014;76:27 [CrossRef] | [Google Scholar]
- Huang Y, Mucke L, Kelley BJ, Knopman DS. Alzheimer mechanisms and therapeutic strategies. Cell. Alternative medicine and Alzheimer’s disease Neurologist. 2012:299 [CrossRef] | [Google Scholar]
- Anekonda TS, Reddy PH. Can herbs provide a new generation of drugs for treating Alzheimer’s disease?. Brain Res Brain Res Rev. 2005;50(2):361-76. [PubMed] | [CrossRef] | [Google Scholar]
- Izzo AA, Capasso F. Herbal medicines to treat Alzheimer’s disease. Trends Pharmacol Sci. 2007;28(2):47-8. [PubMed] | [CrossRef] | [Google Scholar]
- Howes MJR, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res. 2003;17(1):1-18. [PubMed] | [CrossRef] | [Google Scholar]
- Onofrio D G, Sancarlo D, Ruan Q, Yu Z, Panza F, Daniele A, et al. Phytochemicals in the treatment of Alzheimer’s disease: a systematic review. Curr Drug Targets. 2016:17 [CrossRef] | [Google Scholar]
- Ansari N, Khodagholi F. Natural products as promising drug candidates for the treatment of Alzheimer’s disease: molecular mechanism aspect. Curr Neuropharmacol. 2013;11(4):414-29. [PubMed] | [CrossRef] | [Google Scholar]
- Perry EK, Pikering AT, Wang WW. Medicinal plants and Alzheimer’s disease: from etnobotany to phytotherapy. J Pharm Pharmacol. 1999;51:527-34. [CrossRef] | [Google Scholar]
- Ghorbani A, Esmaeilizadeh M. Pharmacological properties of Salvia officinalis and its components. J Trad Complement Med. 2017;7(4):433-40. [PubMed] | [CrossRef] | [Google Scholar]
- Speers AB, García-Jaramillo M, Feryn A, Matthews DG, Lichtenberg T. Centella asiatica Alters metabolic pathways associated with Alzheimer’s disease in the 5xFAD mouse model of ß-amyloid accumulation. Front Pharmacol. 2021;12:788312 [PubMed] | [CrossRef] | [Google Scholar]
- Uddin MJ, Zidorn C. Traditional herbal medicines against CNS disorders from Bangladesh. Nat Prod Bioprospect. 2020;10(6):377-410. [PubMed] | [CrossRef] | [Google Scholar]
- Nataraj J, Manivasam T, Thenmozhi A.J, Essa M.M. Neurochem. Res. Traditional Herbal Medicines Against CNS Disorders from Bangladesh. Natural Products and Bioprospecting. 2020;10:377-410. [PubMed] | [CrossRef] | [Google Scholar]
- Uddin SN. Traditional uses of Ethnomedicinal plants of the Chittagong Hill Tracts. 2006:992 [CrossRef] | [Google Scholar]
- Khan NA, Rashid RM, Afr J. Tradit Complement Altern Med. 2006;3(105):37-47. [CrossRef] | [Google Scholar]
- Azam FMS, Biswas A, Mannan A, Afsana NA, Jahan R, Rahmatullah M, et al. J Evid Based Complement Altern Med. 2014:1-28. [CrossRef] | [Google Scholar]
- Perry N, Court G, Bidet N, Court J, Perry E. European herbs with cholinergic activities: Potential in dementia therapy. Int J Geriatr Psychiatr. 1996;11:1063 [CrossRef] | [Google Scholar]
- Orhan I, Sener B, Choudhary MI, Khalid A. Acetylcholinesterase and butyrylcholinesterase inhibitory activity of some Turkish medicinal plants. J Ethnopharmacol. 2004;91(1):57-60. [PubMed] | [CrossRef] | [Google Scholar]
- Matsuda H, Murakami T, Kishi A. Structures of withanosides I, II, III, IV, V, VI, and VII, new withanolide glycosides, from the roots of Indian Withania somnifera DUNAL and inhibitory activity for tachyphylaxis to clonidine in isolated guinea-pig ileum. Bioorg Med Chem. 2001;9(6):1499-507. [CrossRef] | [Google Scholar]
- Laphookhieo S, Phungpanya C, Tantapakul C, Techa S, Tha-in S, Narmdorkmai S, et al. Chemical constituents from Aegle marmelos. J Braz Chem Soc. 2011;22(1):176-8. [CrossRef] | [Google Scholar]
- Islam MH, Ahmad IZ, Salman MT. Neuroprotective effects of Nigella sativa extracts during germination on central nervous system. Pharmacogn Mag. 2015;11(Suppl 1):S182-9. [PubMed] | [CrossRef] | [Google Scholar]
- Jamal Y, Irawati P, Fathoni A, Agusta A. Chemical constituents and antibacterial effect of essential oil of javaneese pepper leaves (Piper retrofractum vahl). Media Litbangkes. 2013;23(2):65-72. [CrossRef] | [Google Scholar]
- Ingkaninan K, Temkitthawon P, Chuenchom K, Yuyaem T, Thongnoi W. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol. 2003;89(2-3):261-4. [PubMed] | [CrossRef] | [Google Scholar]
- Pang Y, Wang D, Fan Z, chen X, Yu F, Hu X, et al. Blumea balsamifera—A phytochemical and pharmacological review. Molecules. 2014;19(7):9453-77. [PubMed] | [CrossRef] | [Google Scholar]
- Eubanks LM, Rogers CJ, Beuscher AE, Koob GF, Olson AJ, Dickerson TJ, et al. Traditional herbal medicines against CNS disorders from Bangladesh. Mol Pharm. 2006;3:773-7. [CrossRef] | [Google Scholar]
- Yadav E, Mani M, Chandra P, Sachan N, Ghosh AK. A review on therapeutic Potential of Lygodium flexuosum Linn. Pharmacogn Rev. 2012;6(12):107-14. [PubMed] | [CrossRef] | [Google Scholar]
- Ragasa YC, Lorena GS, Mandia EH, Raga DD, Shen CC. Chemical constituents of Abrus precatorius. Am J Essent Oils Nat Prod. 2013;1(2):7-10. [PubMed] | [CrossRef] | [Google Scholar]
- Owokotomo IA, Ekundayo O, Oguntuase BJ. Chemical constituents of the Leaf, stem, Root and seed essential oils of Aframomum melegueta (K. Schum) from south West Nigeria. IRJPAC. 2014;4(4):395-401. [CrossRef] | [Google Scholar]
- Maroy AAA. Botany, medicinal uses, phytochemistry, and pharmacological properties. Sci World J. 2018:18 Article ID 7463584 [CrossRef] | [Google Scholar]
- Sampath Kumar KP, Bhowmik D, Chiranji B, Biswajit Array, Tiwari P. Allium cepa: A traditional medicinal herb and its health benefits. J Chem Pharm Res. 2010;2(1) 7384:283-291ISSN : 0975 [CrossRef] | [Google Scholar]
- Mubo AS, Ibukun OA. Medicinal plants used in the treatment of neurodegenerative disorders in some parts of Southwest Nigeria. Afr J Pharm Pharmacol. 2015;9(38):956-65. [CrossRef] | [Google Scholar]
- Goswami S, Saoji A, Kumar N, Thawani V, Tiwari M, Thawani M, et al. Effect of Bacopa monnieri on Cognitive functions in Alzheimer’s disease patients. Int J Collab Res Intern Med Public Health. 2011;3(285):93 [CrossRef] | [Google Scholar]
- Agyare C, Oguejiofor S, Bekoe OE, Amoah LA, Boakye YD. Anti-inflammatory and anti-infective Properties of ethanol Leaf and Root Extracts of Baphia nitida. BMRJ. 2016;11(4):1-7. Article no.BMRJ.22459 [CrossRef] | [Google Scholar]
- Abdullahi M, Buhari F, Abdulrauf S. Antimicrobial activity of Bombax buonopozense P. Beauv. (Bombacaceae) Edible Floral Extracts. Eur J Sci Res. 2011:627-630. ISSN 1450-216X;48(4) [CrossRef] | [Google Scholar]
- Kumar KM, Sharma A, Dhiman A. Medicinal potential of Digitaria: An overview. J Pharmacogn Phytochem. 2021;10(1):1717-9. [CrossRef] | [Google Scholar]
- Victor OB, Owolabi GO. Traditional oil palm (Elaeis guineensis jacq.) and its medicinal uses. A review. 2014;4(3):16 [CrossRef] | [Google Scholar]
- Satya R, Narain SR, Rawat A, Kaur J, Kumar S, Fatima N, et al. Taxonomy, phytochemistry, pharmacology and traditional uses of Flueggea virosa (Roxb. ex Willd.) Royle. A Review. Int J Life Sci. 2018;6(2):579-85. [CrossRef] | [Google Scholar]
- Abobatta WF. Jatropha curcas: an overview Journal of Advances in Agriculture. 2019:2349-0837. [CrossRef] | [Google Scholar]
- Corrêa GM, De AF, Alcântara C. Chemical constituents and biological activities of species of Justicia – a review. Rev Bras Farmacognosia Braz J Pharmacogn. 2012;22(1):220-38. [CrossRef] | [Google Scholar]
- Vassetti A, Paradisiaca L. Musa sapientum L.: A Phytochemical and Pharmacological Review. J Appl Pharm Sci. 2011:14-20. [CrossRef] | [Google Scholar]
- Ahmad MH, Jatau A, Alshargi AY, Julde SM, Mohammed M, Muhammad S, et al. Ethnopharmacological uses, phytochemistry, pharmacology, and toxicology of Olax subscorpioidea Oliv. (Olacaceae): A review.. Future J Pharm Sci. 2021:7-11. [CrossRef] | [Google Scholar]
- Isikhuemen EM, Ogbomwan BO, Efenudu IU. Evaluation of phytochemical and mineral constituents of Piper guineense Schum. and Thonn. and Piper umbellatum Linn: implications for ethnomedicine. Eur J Med Plants. 2020;31(1):84-97. Article no EJMP 54232 [CrossRef] | [Google Scholar]
- Amoateng P, Quansah E, Karikari TK. Medicinal plants used in the treatment of mental and neurological disorders in Ghana evidence-based complementary and alternative medicine volume .2018; 14. ;0381 Article ID 8590381.https://doi.org/10.1155/2018/859 [CrossRef] | [Google Scholar]
- Mahdy K, Shaker O, Wafay H, Nassar Y, Hassan H, Hussein A, et al. Effect of some medicinal plant extracts on the oxidative stress status in Alzheimer’s disease induced in rats. Eur Rev Med Pharmacol Sci. 2012;16(Suppl 3):31-42. [PubMed] | [Google Scholar]
- Attah AF, Hellinger R, Sonibare MA, Moody JO, Arrowsmith S, Wray S, et al. Ethnobotanical survey of Rinorea dentata (Violaceae) used in South-Western Nigerian ethnomedicine and detection of cyclotides. J Ethnopharmacol. 2016;179:83-91. [PubMed] | [CrossRef] | [Google Scholar]
- Elufioye TO, Obuotor EM, Agbedahunsi JM, Adesanya SA. Anticholinesterase constituents from the leaves of Spondias mombin L. (Anacardiaceae). Biologics. 2017;11:107-14. [PubMed] | [CrossRef] | [Google Scholar]
- Swarna J, ravindhran R. Parmacognostical and phytochemical evaluation of Talinum triangulare (jacq.) willed. Int J Pharm Pharm Sci. 2013;5(2):249-56. [PubMed] | [CrossRef] | [Google Scholar]
- Zaveri M, Khandhar A, Patel S. Patel. A chemistry and pharmacology of Piper longum. Int J Pharm Sci Rev Res. 2010;5 Article-010 [PubMed] | [CrossRef] | [Google Scholar]
- Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti– inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40-59. [PubMed] | [CrossRef] | [Google Scholar]
- Sharma P, Bharat P, Dwivedee D, Bisht AK, Dash D, Kumar Array, et al. The chemical constituents and diverse pharmacological importance of Tinospora cordifolia. Heliyon. 2019:e024373 [CrossRef] | [Google Scholar]
- Jae L, Kyung L, Beom J. Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O–methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid. Pharmacol Biochem Behav. 2009;95(1):31-40. [CrossRef] | [Google Scholar]
- Tafuri S, Cocchia N, Carotenuto D, Vassetti A, Staropoli A. Chemical Analysis of Lepidium meyenii (Maca) and its Effects on Redox Status and on Reproductive Biology in Stallions †. Molecules. Array;24(10) [PubMed] | [CrossRef] | [Google Scholar]
- El-Saber Batiha G, Magdy Beshbishy A, El-Mleeh A, Abdel-Daim MM, Prasad Devkota H1A. Traditional uses, bioactive chemical constituents, and pharmacological and toxicological activities of Glycyrrhiza glabra L. (Fabaceae). Biomolecules. 2020;10(3):352 [PubMed] | [CrossRef] | [Google Scholar]
- Zhang Z, Wang X, Chen Q, Shu L, Wang J, Shan G, et al. Clinical efficacy and safety of huperzine alpha in treatment of mild to moderate Alzheimer disease. A placebo-controlled, double-blind, randomized trial. Zhonghua Yi Xue Za Zhi. 2002;82(14):941-4. [PubMed] | [Google Scholar]
- Tomoharu K, Chihiro T, Katsuko K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. B. J Pharmacol. 2005;144:961-71. (PMC Free article). PMID PubMed, Google Scholar [PubMed] | [Google Scholar]
- Jayaprakasam B, Padmanabhan K, Nair MG. Withanamides in Withania somnifera fruit protect PC-12 cells from β-amyloid responsible for Alzheimer’s disease. Phytother Res. 2010;24(6):859-63. [PubMed] | [CrossRef] | [Google Scholar]
- Dubey GP, Pathak SR, Gupta BS. Combined effect of Brahmi (Bacopa monniera) and Shankhpushpi (Convolvulus pluricaulis) on cognitive functions. Pharmacopsychoecol. 1994;7:249-51. Google Scholar [PubMed] | [CrossRef] | [Google Scholar]
- Bhanumathy M, Harish MS, Shivaprasad HN, Sushma G. Nootropic activity of Celastrus paniculatus seed. Pharm Biol. 2010;48(3):324-7. [PubMed] | [CrossRef] | [Google Scholar]
- Walesiuk A, Braszko JJ. Preventive action of Ginkgo biloba in stress- and corticosterone-induced impairment of spatial memory in rats. Phytomedicine. 2009;16(1):40-6. [PubMed] | [CrossRef] | [Google Scholar]
- Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998;112(5):1199-208. Google Scholar [PubMed] | [CrossRef] | [Google Scholar]
- Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 2006;27(1):1-26. [PubMed] | [CrossRef] | [Google Scholar]
- Eidi M, Eidi A, Bahar M. Effects of Salvia officinalis L. (sage) leaves on memory retention and its interaction with the cholinergic system in rats. Nutrition. 2006;22(3):321-6. [PubMed] | [CrossRef] | [Google Scholar]
- Obulesu M, Rao DM. Effect of plant extracts on Alzheimer’s disease: An insight into therapeutic avenues. J Neurosci Rural Pract. 2011;2(1):56-61. (PMC Free article) [PubMed] | [CrossRef] | [Google Scholar]
- Pramodinee D, Mahesh M, Niranjan D, Sankpala S. Memory enhancing activity of Cissampelos papiera in mice. Int J Pharm Sci. 2011;3:206-11. Google Scholar [PubMed] | [CrossRef] | [Google Scholar]
- Dhanasekaran M, Tharakan B, Holcomb LA, Hitt AR, Young KA, Manyam BV, et al. Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera. Phytother Res. 2007;21(10):965-9. [PubMed] | [CrossRef] | [Google Scholar]
- Saxena V, Ahmad H, Gupta R. Memory enhancing effects of Ficus carica leaves in hexane extract on interoceptive behavioral models. Asian J Pharm Clin Res. 2013;6:109-13. Google Scholar [PubMed] | [CrossRef] | [Google Scholar]
- Lu JH, Ardah MT, Durairajan SSK, Liu LF, Xie LX. Baicalein inhibits formation of α-synuclein oligomers within living cells and prevents Aβ peptide fibrillation and oligomerisation. Chem Bio Chem. 2011;12(4):615-24. [PubMed] | [CrossRef] | [Google Scholar]
- Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Multifunction of myricetin on A beta: Neuroprotection via a conformational change of A beta and reduction of A beta via the interference of secretases. J Neurosci Res. 2008;86(2):368-77. [PubMed] | [CrossRef] | [Google Scholar]
- Ramezani M, Darbandi N, Khodagholi F, Hashemi A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer’s disease. Neural Regen Res. 2016;11(12):1976-80. [PubMed] | [CrossRef] | [Google Scholar]
- Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S. A berberine alters the processing of Alzheimer’s amyloid precursor protein to decrease Aβ secretion. Biochem Biophys Res Commun. 2007;352(2):498-502. [PubMed] | [CrossRef] | [Google Scholar]
- Jung HA, Min BS, Yokozawa T, Lee JH, Kim YS, Choi JS, et al. Anti-alzheimer and antioxidant activities of Coptidis rhizoma alkaloids. Biol Pharm Bull. 2009;32(8):1433-8. [PubMed] | [CrossRef] | [Google Scholar]
- Descamps O, Spilman P, Zhang Q, Libeu CP, Poksay K, Gorostiza O, et al. AβPP-selective BACE inhibitors (ASBI): novel class of therapeutic agents for Alzheimer’s disease. J Alzheimers Dis. 2013;37(2):343-55. [PubMed] | [CrossRef] | [Google Scholar]
- Qi C, Bao J, Wang J, Zhu H, Xue Y. Asperterpenes A and B, two unprecedented meroterpenoids from Aspergillus terreus with BACE1 inhibitory activities. Chem Sci. 2016;7(10):6563-72. [PubMed] | [CrossRef] | [Google Scholar]
- Mori T, Koyama N, Guillot-Sestier MV, Tan J, Town T. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice. PLOS ONE. 2013;8(2) Article ID e55774 [PubMed] | [CrossRef] | [Google Scholar]
- Srinivasan M, Sudheer AR, Menon VP. Ferulic acid: therapeutic potential through its antioxidant property. J Clin Biochem Nutr. 2007;40(2):92-100. [PubMed] | [CrossRef] | [Google Scholar]
- Youn K, Jun M. Biological evaluation and docking analysis of potent BACE1 inhibitors from Boesenbergia rotunda. Nutrients. 2019;11(3):662 [PubMed] | [CrossRef] | [Google Scholar]
- James S, Aparna JS, Paul AM, Lankadasari MB, Mohammed S, Binu VS, et al. Cardamonin inhibits colonic neoplasia through modulation of microRNA expression. Sci Rep. 2017;7(1):13945 [PubMed] | [CrossRef] | [Google Scholar]
- Chen W, Chen G. Danshen (Salvia miltiorrhiza Bunge): A Prospective Healing Sage for Cardiovascular Diseases. Curr Pharm Des. 2017;23(34):5125-35. [PubMed] | [CrossRef] | [Google Scholar]
- Tang Y, Huang D, Zhang MH, Zhang WS, Tang YX, Shi ZX, et al. Salvianolic acid B inhibits Aβ generation by modulating BACE1 activity in SHSY5Y- APPsw cells. Nutrients. 2016;8(6):333 [PubMed] | [CrossRef] | [Google Scholar]
- Tian J, Liu Y, Chen K. Ginkgo biloba extract in vascular protection: Molecular mechanisms and clinical applications. Curr Vasc Pharmacol. 2017;15(6):532-48. [PubMed] | [CrossRef] | [Google Scholar]
- Khoury R, Grysman N, Gold J, Patel K, Grossberg GT. The role of 5 HT6-receptor antagonists in Alzheimer’s disease: An update. Expert Opin Investig Drugs. 2018;27(6):523-33. [PubMed] | [CrossRef] | [Google Scholar]
- Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. Antioxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease. Antioxidants (Basel). 2018;7(5):63 [PubMed] | [CrossRef] | [Google Scholar]
- Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: An overview of systematic reviews. J Ethnopharmacol. 2017;195:1-9. [PubMed] | [CrossRef] | [Google Scholar]
- Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M, et al. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther. 2003;28(1):53-9. [PubMed] | [CrossRef] | [Google Scholar]
- Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S, Jamshidi AH, Khani M, et al. Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: A double blind, randomised, placebo controlled trial. J Neurol Neurosurg Psychiatry. 2003;74(7):863-6. [PubMed] | [CrossRef] | [Google Scholar]
- Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M. A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J Clin Psychiatry. 2005;66(2):248-52. [PubMed] | [CrossRef] | [Google Scholar]
- Iwasaki K, Kobayashi S, Chimura Y, Taguchi M, Inoue K. A randomized, double-blind, placebo-controlled clinical trial of the Chinese herbal medicine “ba wei di huang wan” in the treatment of dementia. J Am Geriatr Soc. 2004;52(9):1518-21. [PubMed] | [CrossRef] | [Google Scholar]
