ALZHEIMER’S DISEASE: A CHALLENGE IN MANAGING WITH CERTAIN MEDICINAL PLANTS – A REVIEW

ALZHEIMER’S DISEASE: A CHALLENGE IN MANAGING WITH CERTAIN MEDICINAL PLANTS - A REVIEW

G. K. Pratap, S. Ashwini and Manjula Shantaram^*

Department of Studies in Biochemistry, Mangalore University, Post Graduate Centre, Chikka Aluvara - 571232, Kodagu, Karnataka, India.

ABSTRACT: It is well known that some plants have medicinal properties and their knowledge has been accumulated in the course of many centuries, based on different medicinal systems such as Ayurveda, Unani and Siddha. In India, it is reported that traditional healers use nearly 2,500 plant species and 100 plant species serve as regular sources of medicine for the treatment of various diseases. Alzheimer’s disease is globally recognized as the most common form of dementia and it disrupts critical metabolic processes which keep neurons healthy. These disruptions cause nerve cells in the brain to stop working, lose connections with other nerve cells and finally die. The destruction and death of nerve cell causes the memory failure, personality changes and problems in carrying out daily activities. The Alzheimer’s disease has an abundance of two abnormal structures- amyloid plaques and neurofibrillary tangle. The Alzheimer’s disease is caused by a mixture of genetic, environmental, and life style factors. The current review methodically summarizes the Alzheimer’s disease and the effects of phyto-chemicals of medicinal plants in various models of Alzheimer’s disease.

Alzheimer’s disease, Dementia, Amyloid plaques, Neurofibrillary tangle

INTRODUCTION: Alzheimer’s disease (AD) was the eighth-leading cause of death in 2001. It was discovered in 1906 by Alois Alzheimer, a German neurologist and psychiatrist. However, there was no cure and no effective treatment for it ¹. AD is a progressive neurodegenerative disease resulting in the gradual decline of a person’s memory and ability to learn reason, make judgements, communicate, and carry out daily activities ². AD is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, eventually even the ability to carry out the simplest tasks.

It is a progressive dementia disorder in an elderly population. The pathology includes accumulation of amyloid β-peptide (Aβ), neuro-inflammation and oxidative damage in the brain ³. The nervous system is a complex network of nerve cells, which regulates body’s voluntary and involuntary actions and transmits nerve impulses between different parts of the body.

Research in Alzheimer’s disease has provided the intellectual framework for therapeutic intervention. It proposes that the deposition of β-amyloid is the initial pathological event in AD leading to the formation of senile plaques and then to neurofibrillary tangles, neuronal cell death, and ultimately causes dementia ⁴. Alzheimer’s disease is globally recognized as the most common form of dementia, with multiple studies projecting that by the year 2050, approximately 115 million people will be affected worldwide ⁵. The effect of cholesterol in the development of AD apart from mutations in the proteins involved in amyloid-β generation (ßAPP- ß- Amyloid precursor protein, presenilins), the strongest known risk factor influencing the incidence of sporadic AD is the genotype for apolipoprotein E (ApoE), the major carrier of cholesterol in the Central Nervous System (CNS). Individuals carrying one or two copies of the ApoE-e4 allele have a higher risk of developing the disease, compared to those carrying the e3 (the most common) or e2 (which appears to be protective) forms ⁶.

Methodology: Well-known scientific search engines namely, Google Scholar, PubMed, EMBASE, Mendeley, Science Direct, standard books, Springer Link were used to retrieve online literature. The results are cross-referenced to generate a total number of 95 references cited in this review, during the time span of 1993 - 2016. The current review methodically summarizes the Alzheimer’s disease, effects of phytochemicals of medicinal plants in various models. Table 2 represents the plants, parts used, active compound, mode of extraction and their mode of action in AD therapy. The pictures represent the stages of Alzheimer’s disease and aging of brain (Fig. 1) and the difference between normal brain and Alzheimer’s disease brain (Fig. 2 and 3).The difference between normal neuron and Alzheimer’s disease-infected neuron, also accumulation of beta amyloid precursor protein in neurons is shown in Fig. 4.

Factors Affecting Alzheimer’s disease: While scientists know that Alzheimer’s disease involves the failure of nerve cells, the reason behind this is unknown. However, they have identified certain risk factors that increase the likelihood of developing AD.

Age: The greatest known risk factor for Alzheimer’s disease is increasing age. Most individuals with the illness are 65 years and older. One in nine people in this age group and nearly one-third of the people who are 85 years and older have Alzheimer’s.

Family History: Another risk factor is family history. Research has shown that those who have a parent, brother or a sister with Alzheimer’s are more likely to develop the disease than individuals who do not. The risk increases if more than one family member has the illness ⁷.

Obesity: It was observed that the obesity at midlife may increase the risk of dementia and AD later in life. Further, the association was weakened by adjustment for other vascular risk factors and diseases, indicating that the effect of obesity on dementia might be partly mediated through these vascular factors. Nevertheless, midlife obesity, high systolic blood pressure and high total cholesterol level were all significant risk factors for dementia, each of them increasing the risk around twice ⁸.

Researchers have noted a clustering of cardiovascular risk factors, termed syndrome X or the metabolic cardiovascular syndrome. Factors commonly included in this syndrome are hypertension, obesity, dyslipidemia and glucose intolerance. Development of these risk factors is thought to reflect a common underlying pathology. The syndrome leads to an increased risk of diabetes and cardiovascular disease. Both these clinical conditions have been linked to an increased risk of vascular dementia (VaD) and AD ⁹.

Genetics:

The Alzheimer’s disease can be Caused Due to Mutations in the APP Gene: The apolipoprotein E locus (APOE) on chromosome 19 APOE-e2, APOE-e3 and APOE-e4 is observed. A total of 80% of familial and 64 % of sporadic AD late onset cases have at least one APOE-e4 compared to 31 % of control subjects ¹⁰. Autosomal dominant forms of Alzheimer’s disease represented only 5 % of all Alzheimer’s disease cases. Most AD patients have the sporadic form of the disease but for these Alzheimer’s disease cases, genetic susceptibility factors could also increase or decrease the risk of developing the disease ¹¹.

Sex: The overall incidence of Alzheimer’s disease was similar in men and women. Over the age of 90 years the incidence of Alzheimer’s disease was higher for women than men. The risk of vascular dementia was higher for men than women across all age groups. Both studies found that the incidence of dementia and Alzheimer’s disease continued to increase with age up to 85 - 90 years, after which rates increased in women but not in men ¹². The prominent rise in incidence rates of dementia in the very old appear due to Alzheimer's disease, while rates for vascular dementia remains moderately constant. These inclinations are particularly marked for minimal dementia, but emphasize the importance of Alzheimer's disease in the community as an origin of cognitive decline of all degrees ¹³.

Smoking: Smoking had a substantial relationship for increased risk of Alzheimer's disease. Smoking increases cardiovascular risk and nicotine may alter reaction time, learning and memory. Cardio vascular risk factors have been linked to augmented risk of dementia. A previous study found that the fresh smokers were found to be at higher risk of subsequent dementia, Alzheimer's disease, vascular dementia and cognitive decline ¹⁴.

Alcohol Consumption: Some studies have shown that heavy alcohol consumption might be associated with an increased risk of dementia in patients with mild cognitive impairment or in men carrying the APOE-e4allele ¹⁵. Given the link between VaD, vascular function, and the increasing body of evidence suggesting that AD may be influenced by vascular factors, it may be concluded that this cardiovascular protection decreases incident dementia/cognitive decline. Counter to this are the effects of heavy alcohol consumption and alcoholism as detrimental to memory function ¹⁶.

Education: Poor education was cited as a risk factor for Alzheimer’s disease, especially in males. Better education may reveal greater cognitive capacity and reserve, thus postponing the onset of the illness. Similar arguments apply to the size of the head and dementia risk. It is not clear whether it is the learning obtained in childhood or the life-time procurement of knowledge that is protective. Supposing the latter, a trial of cognitive training in individuals at risk of dementia is currently running in the USA ¹⁷.

Tau Protein: Tau is one of the microtubules associated with protein that are thought to have a role in the stabilization of neuronal microtubules these in turn provide the track for intracellular transport ¹⁸.The molecular mechanisms governing tau aggregation are mainly represented by several post-translational modifications that modify its structure and conformational state.

Hence, abnormal phosphorylation and truncation of tau protein have gained attention as crucial mechanisms that become tau protein in a pathological unit ¹⁹. After neuronal damage, tau is released into extracellular space and may be increased in the cerebrospinal fluid (CSF). Elevated CSF levels of tau occur in parenchymal diseases, including neurodegenerative as well as vascular or inflammatory diseases ²⁰.

Oxidative Stress and β-amyloid: Oxidative stress plays a substantial role in the pathogenesis of AD, a damaging disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation and β-amyloid peptides. Oxidative stress participates in the development of AD by promoting amyloid -β deposition, tau hyper-phosphorylation and the successive loss of synapses and neurons ²¹.

The amyloid precursor protein observed in Alzheimer's disease pathology, suggests a time-course of plaque development beginning with neuronal amyloid precursor protein accumulation, then deposition into the extracellular space, subsequent processing by astrocytes or microglia, and resulting in beta-amyloid peptide accumulation in plaques ²².

APP can be proteolyzed directly by α-secretase and then γ-secretase, a process that does not generate amyloid-β, or reinternalized in clathrin -coated pits into another endosomal compartment containing the proteases BACE1 and γ-secretase. The latter results in the production of amyloid-β ²³.

Phases of Alzheimer’s disease: Alzheimer’s disease typically progresses slowly in three general stages early, middle, later. Since Alzheimer’s disease affects different way, each person may experience symptoms or progress through the different way ²⁴.

Preclinical Stage: This mild stage, which usually lasts 2 to 4 years, is often when the disease is first diagnosed. In this stage, family and friends may begin to realize that there has been a deterioration in the patient’s cognitive ability. Common symptoms at this stage were included ⁷. Difficulty holding new information, difficulty with problem solving or decision making. Patients may start to have trouble managing finances or other instrumental activities of daily living which show personality changes. The person may begin to withdraw socially or show lack of motivation and difficulty in conveying thoughts. Further, mislaying belongings or getting lost. The patient may have trouble navigating in familiar surroundings ²⁵.

TABLE 1: DIFFERENT STAGES OF ALZHEIMER’S ²⁶

Clinical criteria for Mild Cognitive Impairment (MCI): Subjective cognitive complaint, preferably collaborated by an informant objective memory and/or other cognitive impairments that a) are abnormal for the individual’s age and education, as documented using neuropsychological testing b) represent a decline from previous levels of functioning, decline in the normal ability to perform activities of daily living but absence of dementia ²⁸.

FIG. 1: THE STAGES OF ALZHEIMER’S DISEASE AND AGING OF BRAIN

Model of the clinical trajectory of AD. The stage of preclinical AD precedes mild cognitive impairment (MCI) and encompasses the spectrum of pre-symptomatic autosomal dominant mutation carriers, asymptomatic biomarker-positive older individuals at risk for progress into MCI due to AD and AD dementia, as well as biomarker-positive individuals who have demonstrated subtle decline from their own baseline that exceeds the expected in typical aging, but would not yet meet criteria for

MCI. Note that this diagram represents a hypothetical model for the pathological-clinical continuum of AD but does not imply that all individuals with biomarker evidence of AD-pathophysiological process will progress to the clinical phases of the illness ²⁹.

The Alzheimer’s disease is a progressive neuro-degenerative brain disorder it causes a major trouble of normal brain structure and function ³¹.

FIG. 2: DIFFERENCE BETWEEN NORMAL AND ALZHEIMER’S DISEASE BRAIN ³⁰ Alzheimer’s disease results in shrinkage of brain regions involved in learning and memory which is correlated with major reductions in cellular energy metabolism in living patients. A) Compared with the brain of a healthy person, the brain of an Alzheimer’s disease patients exhibits marked shrinkage of gyri in the temporal lobe (lower part of the brain) and frontal lobes (left part of the brain). B) Positron emission tomography (PET) images showing glucose uptake (red and yellow indicates high levels of glucose uptake) in a living healthy person and a normal conrol subjects. The Alzheimer’s patients exhibits large decrease in energy metabolism in the frontal cortex ( top of brain) and temporal lobes (sides of the brain)

FIG. 3: AD SPREADS THROUGH THE BRAIN ³¹

Control Measures in Alzheimer’s to lower the Risk of Dementia: ³² The prevention of AD is major public health face, but numerous promising therapies targeting β-amyloid have unsuccessful in late stage clinical trials.

Quit Smoking: Smoking causes a great damage to the body, including the brain. According to studies, daily smokers are at a 45 % higher risk of developing Alzheimer’s in comparison to non-smokers and ex-smokers. Hence, it is strongly advised to quit this detrimental habit ³³.

Vitamin B: B Vitamins reduce the levels of a molecule known as homocysteine (HC), which harms the vascular system. When in elevated levels, it increases the risk of strokes, heart diseases, and other vascular problems. Having a higher intake and blood level of Vitamin B12 and folic acid, is associated with a part of the risk of developing Alzheimer’s. Vitamin B6, B12 and folic acid, especially in combination, lower the blood levels of homocysteine, which is a key predictor of risk ³⁴.

Vitamin D: Researchers have found a link between the reduced levels of Vitamin D and cognitive decline, causing dementia symptoms. Therefore, the use of Vitamin D supplements, prevents processes that contribute to dementia and Alzheimer’s ³⁵.

Control of Alcohol Intake: The excessive alcohol use raises the risk of dementia, so it has to be controlled in order to prevent various health issues, including dementia ³³. Staying cognitively active throughout life via social engage­ment or intellectual stimulation is associated with a lower risk of Alzheimer’s disease ³⁶.

Diet: A number of studies suggest that eating certain foods may help keep the brain healthy and

that others can be detrimental to cognitive health. A diet that includes lot of fruits, vegetables and whole grains and is low in fat and added sugar can reduce the risk of many chronic diseases, including heart disease and type 2 diabetes. Researchers are looking at whether a healthy diet also can help preserve cognitive function or reduce the risk of Alzheimer’s ³⁵.

Neuroprotection: Neuroprotection is a broad term to cover any therapeutic strategy to prevent nerve cells called neurons from dying and it usually involves an intervention, either a drug or treatment ³⁶. Neuroprotection is commonly used to refer to any type of therapeutic strategy, usually pharmacological, that can prevent, delay or even reverse neuronal damage, whether it be neuronal death, axonal degeneration or any other form of neuronal injury. Neuroprotective strategies presently being evaluated including acetylcholinesterase inhibitor, glutamate antagonists, calcium channel blockers, nitric oxide synthase inhibitors and so on ³⁷.

Herbal Neuroprotection: Several parts of the herbal plants such as roots, leaves, stems, barks, flowers and fruits are commonly rich in phenolic compounds and other secondary metabolites ⁵. The pharmacological property of each compound differed in their active principles and many Indian medicinal plant composites are represented as neuroprotective and neuro-pharmacologically active compounds ³⁸.

The herbs or their preparations (or both)are used to treat CNS disorders ³⁹. A few specific herbs and their active ingredients have been identified in particularly Alzheimer’s neuroprotection (Table 2). Antioxidants are not the only active compounds that may stimulate or sedate the nervous system and those that reduce inflammation also help ⁴⁰.

TABLE 2: PLANTS AND THEIR PHYTOCHEMICALS FOR TREATING ALZHEIMER’S DISEASE

NORMAL                                    ALZHEIMER’S

FIG. 4: THE DIFFERENCE BETWEEN NORMAL NEURON AND ALZHEIMER’S DISEASE INFECTED NEURON⁵⁹

Synthetic drugs for Neuroprotection: Neuronal cells are extremely vulnerable and have a limited capacity for self-repair in response to injury. For those reasons, there is obvious interest in limiting neuronal damage. Mechanisms and strategies used in order to protect against neuronal injury, apoptosis, dysfunction, and degeneration in the central nervous system are recognized as neuroprotection. The neuro-protection could be achieved through several classes of natural and synthetic neuroprotective agents (Table 3).

However, considering the side effects of synthetic neuroprotective agents, the search for natural neuroprotective agents has received a great attention ⁷⁵.

The neurobiological bases of these benefits include the exercise-induced increase in levels of brain-derived neurotrophic factor (BDNF) ⁷⁶ and other growth factors, stimulation of neuro-genesis, increase in resistance to brain insult ⁷⁷ and improvement in learning and mental performance ⁷⁸.

TABLE 3: SYNTHETIC DRUGS OR SUPPLEMENTS USED FOR NEUROPROTECTION

DISCUSSION: The plants used in Indian medicine system are mentioned above in the Table 2. All these plants are used against anti-alzheimer’s, anti-parkinsonism, anti-neuroglia, neuroprotective with memory enhancing property. Some of the phyto-chemical components of these plants are azimine, caepinealkaloids, flavonoids, phenolic compounds, bacosides and nicotine. In recent years, there is a great demand for plant based products because of the broad biological activity. The change in the modern life style and unhealthy food habit have resulted in obesity, diabetes, hyper tension, neurological disorders in a large population. During these conditions, people fully depend on synthetic medicines. However, the long term use of these drugs results in many side effects but natural based products and plant based drugs have no side effects or less side effects.

CONCLUSION: Alzheimer’s disease is the most common cause of dementia, which is becoming more and more frequent in conjunction with growing population. In addition to this, individuals suffering from Alzheimer’s disease is a socio-economic burden in India and other countries which is beyond comparison with any other diseases. Drugs to treat Alzheimer’s disease are very expensive and have side effects. The middle-class family cannot afford to purchase these drugs. But the plant based products are less expensive and without side effects. These drugs may be helpful in enhancing memory in patients. Thus, the knowledge of the medicinal plants helps to develop drugs in modern medicine system.

ACKNOWLEDGEMENT: Authors are grateful to Mangalore University for the support and encouragement.

CONFLICT OF INTEREST: Nil.

REFERENCES

1. Alzheimer’s disease: Unraveling the Mystery,S. Department of Health and Human Services NIH Publication Number: 2008; 08-3782.
2. Seiguer E: Alzheimer’s disease: Research Advances and Medical Reality 2005, Commonwealth Fund pub.https:// www.Cmwf.Org.
3. Soheili M, Taviran MR and Salami M: Clearance of amyloid beta plaques from brain of Alzheimeric rats by Lavandula angustifolia. Neuroscience & Medicine 2012; 3: 362-367. http://www.SciRP.org/journal/nm
4. Phukan P, Bawari M and Sengupta M: Promising neuroprotective plants from North-East India. International Journal of Pharmacy and Pharmaceutical Sciences 2015; 7(3): 0975-1491.
5. Aggarwal NT, Shah RC and Bennett DA: Alzheimer’s disease: Unique markers for diagnosis and new treatment modalities. Indian J Med Res 2015; 369-82.
6. Canevari L and Clark JB: Alzheimer’s disease and cholesterol: The fat connection. Neurochem Res 2007; 32: 739-50.
7. Alzheimer’s Association http://Alz.Org/Education
8. Kivipelto MN, Gandu T, Fratiglioni ML, Viitanen, Kåreholt I, Winblad B, et al., Obesity and Vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005; 62: 1556-60.
9. Foley SKD, White L, Burchfiel CM, Curb JD, Petrovitch GW, Ross RJ et al., Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu-Asia Aging Study. Journal of the American Heart Association’s 2000; 2256-60.
10. Corder EH, Saunder AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al., Gene Dose of Apo lipoprotein E Type 4 Allele and the risk of Alzheimer's disease in late onset families. Sciencemag 1993; 261.
11. Richard F and Amouyel P: Genetic susceptibility factors for Alzheimer’s disease. European Journal of Pharma-cology 2001; 1-12.
12. Ruitenberga A, Otta BA, John C, Swietev V, Hofman A, Monique MB, et al., Incidence of dementia: Does gender make a difference? Neurobiology of Aging 2001; 22: 575-80.
13. Brsyne C, Gill C, Huppert FA, Barkley C , Gehlhaar E, Girling DM, et al., Incidence of clinically diagnosed subtypes of dementia in an elderly population. Cambridge Project for Later Life Incidence of clinically diagnosed subtypes of dementia in an elderly population. Cambridge Project for Later Life1995; 167; 2:255-62.
14. Peters R, Poulter R and Warner J: Smoking, dementia and cognitive decline in the elderly. A systematic review BMC Geriatrics 2008; 8: 1471-2318.
15. Chen JH, Lin KP and Chen YC: Risk factors for dementia. Journal of the Formosan Medical Association 2009; 108: 754-64.
16. Peters R, Peters J, Warner J, Beckett N and Bulpitt C: Alcohol, dementia and cognitive decline in the elderly. A systematic review. Oxford University Press on behalf of the British Geriatrics Society 2008; 37: 505-12.
17. Catriona D, McCullagh CD, Craig D, Stephen P. Mcilroy A and Passmore P: Risk factors for dementia. Advances in Psychiatric Treatment 2001; 7: 24-31.
18. Mandelkow EM and Andelkow K: Tau protein and Alzheimer’s disease. Neurobiology of Aging 1994; 15: 585-6.
19. Kolarova M, ´Ia-Sierra FG, JanRicny AB and Ripova1 D: Structure and pathology of tau protein in Alzheimer disease. International Journal of Alzheimer’s Disease 2012; 13.
20. Sigurd D, Ssmutha S, Reiberb H and Tumania H: Tau protein in Cerebrospinal Fluid (CSF): A blood CSF Barrier related evaluation in patients with various neurological diseases. Neuroscience Letters 2001; 300: 95-98.
21. Chen Z and Zhong C: Oxidative stress in Alzheimer’s disease. Neuroscience bulletin Springer 2014; 30: 271-281.
22. Cummings BJ, Su SH, Geddes JW, Noster V, Wagner SL, Cunningham DD, et al., Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease. Pub med1992; 48: 763-77.
23. Richard J, Philip CB and Wong: Amyloidal precursor protein processing and Alzheimer’s disease. Annual Rev Neuro Sci 2011; 34: 185-204.
24. Alzheimer’s Association Org/Uptodate January 2016
25. Bethune K: Thesis; Diagnosis and treatment of Alzheimer’s disease: Current Challenges 2010.
26. alz.orgUpdatedOctober 2003.
27. Amazing activities for low function abilities and caregiver guide. page 15.www.trafford.com
28. Igor O and Korolev: Alzheimer’s disease. A Clinical and Basic Science Review Medical Student Research Journal 2014; 04.
29. Sperlinga RA, Aisenb PS and Laurel A: Toward defining the preclinical stages of Alzheimer’s disease. Recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for the Journal of the Alzheimer's Association 2011; 280-92.
30. Seiguer E: Alzheimer’s disease: Research Advances and medical reality common wealth Fund publications are available online at www.cmwf.org
31. Alzheimer’s disease Unraveling the Mystery 2008 Nia.Nih.Gov/Alzheimers.
32. Ojo O, rooke JB: Evaluating the association between diabetes, cognitive decline and dementia. J. Environ. Res. Public Health 2015; 12: 8281-94.
33. Free Online Cognitive Function Test foodforthe brain.org.
34. Stem cells molecular medicine cancer biology biotech entrepreneurship.https://www.facebook.com/groups/sheomohan/].
35. National Institute on Aging. https://www.nia.nih.gov/.
36. Alzheimer’s disease Education and Referral (ADEAR) Center. https://www.nia.nih.gov/alzheimers adear@nia.nih.gov.

37. Pandit MK: Neuroprotective properties of some indian medicinal plants. International Journal of Pharmaceutical and Biological Archives 2011; 2: 1374-79.
38. Iriti M, Gelsomina SV and Faoro F: Neuroprotective herbs and foods from different traditional medicines and diets. Molecules 2010; 15: 3517-55.
39. Praseetha PK, Pratheeba, Sundaram LS and Sakthivel G: Plant Based Indian Traditional Medicine for neurodegenerative diseases. A Novel Approach to Treat Alzheimer Int J Pharm Bio Sci2016; 7: 83 -92.
40. Rao RV, Descamps O, John V and Bredesen DE: Ayurvedic medicinal plants for Alzheimer’s disease. A review. Alzheimer’s Research and Therapy 2012; 4: 22.
41. Dharmananda S: Neuroprotective Herbs and Active Constituents Approaches to Preventing Degenerative Diseases. 2005.
42. Phukan P, Bawari M and Sengupta M: Promising neuroprotective plants from North-East India. International Journal of Pharmacy and Pharmaceutical Sciences 2015; l7: 3.
43. Thendral B, Sathiya S, Babu CS, V. Premalakshm I and Sekar T: In-vitro Studies on antioxidant and free radical scavenging activities of Azima tetracantha Lam leaf extracts. Indian Journal of Science and Technology 2010; 5: 0974-6846.
44. Praseetha PK, Pratheeba1, Somasundaram L and Sakthivel L: Plant based indian traditional medicine for neurodegenerative diseases. A Novel Approach to Treat Alzheimer. Int J Pharm Bio Sci 2016; 7: 83- 92.
45. Kumar GP, Kumar KRA and Naveen S: Phytochemicals having neuroprotective properties from dietary sources and medicinal herbs. J Pharmacognosy. 2015; 7: 1.
46. Kumar A, Boone DK, Weisz HA, Bridget A, Capra T, Uchida T et al., Neuroprotective effects of Aframomum melegueta extract after experimental traumatic brain injury. Natural Products Chemistry and Research 2015; 3:2. http://Dx.Doi.Org/.
47. Asaduzzaman MD, Uddin J, Kader MA, Alam AHMK, Rahman AA, Rashid M, et al., In-vitro acetylcholine esterase inhibitory activity and the antioxidant properties of Aegle marmelos leaf extract. Implications for the treatment of Alzheimer’s disease. The Official Journal of the Japanese Psychogeriatric Society 2014; 14: 1-10.
48. Ho CC, Alaganandam K and Hwang LS: Bio-assay guided isolation and identification of anti-alzheimer active compounds from the root of Angelica sinensis. Food Chemistry Elsevier 2009; 1142: 46-252.
49. Saxena G, Singh M, Meena P, Barber S, D Sharma, Shukla S and Bhatnagar M: Neuroprotective effects of Asparagus racemosus Linn. root extract. Experimental and Clinical Evidence. Annals of Neurosciences 2007; 14: 3.
50. Nannepaga JS, Korivi M, Tirumanyam M, Bommavaram M, and Chia-Hua K: Neuroprotective effects of Bacopa monniera whole-plant extract against aluminum-induced hippocampus damagein rats: Evidence from electron microscopic images. Chinese Journal of Physiology 2014; 279-85.
51. Bihaqia SW, Sharma M, Singh AP and Tiwari AM: Neuroprotective Role of Convolvulus pluricaulison aluminium induced neurotoxicity in rat brain. Journal of Ethnopharmacology 2009; 409-15.
52. Pinto N, Alexandre BDS, Neves KRT, Silva AH, Kalyne L, Leal AM et al., Neuroprotective properties of the standardized extract from Camellia Sinensis (Green Tea) and its main bioactive components, epicatechin and epigallocatechin gallate, in the 6-OHDA model of parkinson’s disease. Hindawi Publishing Corporation 2015; 12.
53. Dohare P, Garg P, Sharma NRU, Jagannathan and Ray M: Neuroprotective efficacy and therapeutic window of curcuma oil: In rat embolic stroke model. BMC Complementary and Alternative Medicine 2008; 8: 55.
54. Panjwani D, Mishra and Banji D: Time dependent antioxidant activity of fresh juice of leaves of Coriandrum sativum. International Journal of Pharmaceutical Sciences and Drug Research 2010; 2 (1): 63-6.
55. Dobhal T, Bawa G, Kaur A and Kumar SLH: Herbal medicines and their neuroprotective effects in Alzheimer’s disease and associated symptoms. International Journal of Pharmamedix India 2013; 1: 510-28.
56. Bhavana D and Jyoti K: Centella asiatica. The elixir of life. BMC Complementary and Alternative Medicine 2011; 2: 431-8.
57. Teltumbde AK, Wahurwagh AK, Lonare MK and Nesari TM: Effect of yashtimadhu (Glycyrrhiza glabra) on intelligence and memory function in male adolescents. Sch. J. App. Med. Sci 2013; 1: 90-5
58. Jagtap, Bhise P and Prakya KV: A Phyto pharmacological review on Garcinia indica. International Journal of Herbal Medicine 2015; 3: 02-07.
59. More SV, Kumar H, Kang S, Song SY, Lee K and Choi DK: Advances in neuro-protective ingredients of medicinal herbs by using cellular and animal models of parkinson’s disease. Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine 2013; 15. Http://Dx.Doi.Org/1
60. Roy A, Lakshmi T and Geetha RV: Top three herbs in Alzheimer’s disease - A review. International Journal of Pharma and Bioscience 2011; 2: 362-75.
61. Rakhunde, Saher PB, Ali SA: Neuroprotective effect of Feronia limoniaon ischemia reperfusion induced brain injury in rats. Indian Journal of Pharmacology 2014; 46: 617-21.
62. Pandit NJK and Kim H: Neuroprotective effect of Metaplexis japonica against in-vitro ischemia model. JHAS 2013; 3: 51-5.
63. Sadiq M, Butta, Nazirb A, Sultana MT and Schroe K: ¨Nbmorusalba L: Nature’s. Functional Tonic Trends in Food Science and Technology 2008; 19: 505-12.
64. Yadav SK, Rai SN and Singh SP: Mucuna pruriens shows neuroprotective effect by inhibiting apoptotic pathways of dopaminergic neurons in the paraquat mouse model of parkinsonism. European Journal of Pharmaceutical and Medical Research 2016; 3: 441-51.
65. Siva M, Shanmugam KR, Shanmugam B, Subbaiah GV, Ravi S, Reddy KS and Mallikarjuna K:Ocimum sanctum: a review on the pharmacological properties. International Journal of Basic and Clinical Pharmacology 2016; 5: 558-65.
66. Wenyu Fu, Zhuang W, Zhou S and Wang X: Plant-derived neuroprotective agents in parkinson’s. Am J Transl. Res Disease 2015; 7: 1189-202.
67. Viswanatha S, Swamy AHM, Patel NL, Gadad PC, Koti BC, Patel UM, Thippeswamy AHM and Manjula DV: Neuroprotective activity of Pongamia pinnata in monosodium glutamate-induced neurotoxicity in rats. Int. J Pharm. Sci. Rev 2013; 657-63.
68. Uddln MS, Mammun AA, Hossain MS, Akter F, Iqbal MA and Asaduzzaman M: Exploring. The effect of Phyllanthus emblica On cognitive performance, brain antioxidant markers and acetylcholineesterase activity in rats: Promising Natural Gift for the Mitigation of Alzheimer's disease. Ann Neurosci 2016; 23: 218-29.
69. Vyoma S: An ancient approach but turning into future potential source of therapeutics in Alzheimer’s disease. Int. Res. J. Pharm 2015; 6:1.
70. Kassab RB, Bauomy AA: The neuroprotective efficiency of the aqueous extract of clove (Syzygium aromaticum) in aluminium-induced neurotoxicity. International Journal of Pharmacy and Pharmaceutical Sciences 2014; 6: 503-8.
71. Rajkumar SP, Selvamani S, Latha AN and Dhivya PS: Role of medicinal plants in management of alzheimer’s and neurodegenerative disease. World journal of Pharmaceutical Research 2015; 4: 352-66.
72. Chang CL and Lin CS: Phytochemical composition, antioxidant activity, and neuroprotective effect of Terminalia chebularetzius extracts disease. BMC Complementary and Alternative Medicine 2012; 7.
73. Sarbisheg MI, Heidari Z, Mahmoudzadeh H, Valizadeh SM and Doostkami M: Neuroprotective effects of Withania coagulans root extract on CA1 hippocampus following cerebral ischemia in rats. Avicenna-J-Phytomed 2016; 6(4): 399-409.
74. Bhatnagar M, Sharma D and Salvi M: Neuroprotective Effects of Withania somnifera A possible mechanism. Neurochem Res 2009; 34: 1975-83.
75. Hanaa H, Ahmeda AM, Zaazaab, Bosy A and Motelpb AE: Zingiber officinale and Alzheimer’s disease: Evidences and mechanisms. Int. J Pharm. Sci. Rev 2014; 27: 142-52.
76. Pangestuti R and Kim SK: Neuroprotective properties of chitosan and its derivatives. Molecular Diversity Preservation International. 2010; 8: 2117-28.
77. Harold D: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013; 45(12): 1452-58.
78. Douauda G, Helga B, Refsumb C, Celeste A, Jagerc DE, Jacobye R, et al., Preventing Alzheimer’s disease-related gray matter A by B-Vitamin treatment. PNAS publication: 2013; 110 (23): 9523-28.
79. Ali T, Yoon GH, Shah SA, Lee HY and Kim MO: Osmotin attenuates amyloid beta induced memory impair-ment, tau phosphorylation and neurodegeneration in the mouse Hippocampus nature scientific report 2015; 1-16
80. The hand book of neuroprotection. http://www.springer. com
81. http//www.mentalhealthdaily.com
82. https://focus7shot.com
83. Jeffrey D. Rothstein, Patel S, Melissa R. Regan and Christine:b-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression International weekly journal of science. 2004; 73-7.
84. https://livertox.nih.gov/. modafinilarmodafinil.htm
85. Vaishnav A andLutsep HL: GABA agonist: clome-thiazole. 2002; 18: 5-8.
86. Lilienfeld S: A novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer's disease. CNS Drug Rev 2002; 8: 159-76.
87. Danysz W, Chris GE, Albrecht PHO and Qua SOG: Neuroprotective and symptom-atological action of memantine relevant for Alzheimer’s disease a unified glutamatergic hypothesis on the mechanism of action. Neurotoxicity Research 2000; 2: 85-97.
88. https://www.alzheimers.org.uk
89. Chew SY and Hoke KW: Leong a ligned Protein-polymer composite fibers enhance nerve regeneration. Adv Funct Mater. 2007; 17: 1288-96.
90. Logan AC: Omega-3 fatty acids and major depression: A primer for the mental health professional
91. Alzheimer’s Association. All rights reserved. Alzheimer Drugs Targeting Beta-Amyloid 2006; 2.
92. https://www.phrma.org/site/default/medicines in develop-ment for Alzheimer’s disease2016.
93. https://www.sciencedirect.com
94. The Handbook of Neuroprotection, DOI 10.1007/978-1-61779-049-2_2, 25© Springer Science+Business Media, LLC 2011.
95. Borsook, Becerra L and Fava M: Use of functional imaging across clinical phases in CNS drug development, nature scientific report 2013; 3: 1-19.
    

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    How to cite this article:

    Pratap GK, Ashwini S and Shantaram M: Alzheimer’s disease: a challenge in managing with certain medicinal plants - a review. Int J Pharm Sci Res 2017; 8(12): 4960-72.doi: 10.13040/IJPSR.0975-8232.8(12).4960-72.

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