HERBAL REMEDIES FOR NEURODEGENERATIVE DISORDER (ALZHEIMER’S DISEASE): A REVIEW

HERBAL REMEDIES FOR NEURODEGENERATIVE DISORDER (ALZHEIMER'S DISEASE): A REVIEW

Parul Agarwal*, Shashi Alok, Amreen Fatima and Prem Prakash Singh

Institute of Pharmacy, Bundelkhand University, Jhansi- 284121, Uttar Pradesh, India

ABSTRACT: Alzheimer’s disease, a neurodegenerative disorder is characterized by intense memory loss enough to interfere with social and occupational execution.It is the most general form of dementia, affecting more than 20 million people worldwide. The treatments of Alzheimer's disease are through cholinesterase inhibitors or NMDA-receptor antagonists, while doubts remain about the therapeutic efficacy of these drugs thus herbal medicine product have been used in the cure of Behavioral and Psychological Symptoms of Dementia. The genes play an important role in the development of Alzheimer’s disease. The objective of this article was to show that the herbal medicine is useful in the treatment of cognitive disorders in the elderly. Although some Food and Drug Administration-approved drugs which are available for the treatment of Alzheimer's disease, the outcomes was not good enough, and there is a place for alternative medicine, that is, herbal medicine. Herbal remedies for Alzheimer’s disease have become more and more popular in the recent years, some herbs that is Ginger, Turmeric, Liquorice, Ginseng, Sage, Rosemarry and etc mention below are useful for cognitive impairment of Alzheimer's disease. This paper reviews the clinical effects of a synthetic drugs and herbal medicines for the treatment of Alzheimer's disease.

Neurodegenerative disorder, dementia, Herbal medicine, Synthetic drugs

INTRODUCTION:In the last few years, there has been an exponential growth in the field of herbal medicine and these drugs are gaining popularity both in developing and developed countries because of their natural origin and less side effects. Many traditional medicines in use are derived from medicinal plants, minerals and organic matter ¹. Early humans recognized their dependence on nature for a healthy life and since that time humanity has depended on the diversity of plant resources for food, clothing, shelter, and medicine to cure myriads of ailments.

Led by instinct, taste, and experience, primitive men and women treated illness by using plants, animal parts, and minerals that were not part of their usual diet ². The use of plant-based health products was also increased in other European countries ³. Export–Import Bank reports reveal that the global trade of plant-derived and plant originated products is around US $60 billion (with growth of 7% per annum) where India holds stake of US $1 billion which is expected to reach 3 trillion US$ by the end of 2015 ^{4, 5}.

Disease Profile: Alzheimer's disease (AD) is a progressive inexorable loss of cognitive function associated with the presence of senile plaques in the hippocampal area of the brain. The disease is the most common form of dementing illness among middle-aged and older adults, affecting more than 5 million Americans, a number estimated to increase to 7.7 million by 2030.

Symptoms typically appear after age 60, and some early-onset forms of the disease are linked to a specific genetic defect. Although the etiology is unknown, genetic factors clearly play a role in 10% to 15% of cases ⁶.

Alzheimer's disease is characterized as a progressive neurodegenerative disorder and considered as prominent cause of dementia in the elderly. The main characteristics of this disease are difficulties in household handling routine and cognitive and emotional disturbance in the elderly. Dementia is a loss of brain function that occurs with certain diseases. Alzheimer's disease is one form of dementia that gradually gets worse over time. It affects memory, thinking, and behavior ^[7]. So far, efforts to find a cure for AD have been disappointing, and the drugs currently available to treat the disease address only its symptoms and with limited effectiveness. The underlying pathogenesis is a loss of neurons in the hippocampus, cortex, and subcortical structures ^[8].

FIG. 1:  NEUROLOGICAL DAMAGE LEADS TO THE DECREASE OF CORTICAL AND HIPPOCAMPAL SIZE. The hippocampus is involved in memory processing.

There are two types of AD:

1. Early onset AD: Symptoms appear before age 60. This type is much less common than late onset. However, it tends to get worse quickly. Early onset disease can run in families. Several genes have been identified.
2. Late onset AD: This is the most common type. It occurs in people age 60 and older. It may run in some families, but the role of genes is less clear ⁹.

Causes:

1. Age-related changes in the brain: One of the great mysteries of Alzheimer’s disease is why it largely strikes older adults. Research on how the brain changes normally with age is shedding light on this question. For example, scientists are learning how age-related changes in the brain may harm neurons and contribute to Alzheimer’s damage.
2. Genetics: The more researchers learn about Alzheimer's disease, the more they realize that genes play an important role in its development. Early-onset Alzheimer’s is a rare form of the disease. It occurs in people age 30 to 60 and represents less than 5 percent of all people who have Alzheimer’s disease. Most cases of early-onset Alzheimer’s are familial Alzheimer’s disease, caused by changes in one of three known genes inherited from a parent.

Most people with Alzheimer’s disease have “late-onset” Alzheimer’s, which usually develops after age, 60. Many studies have linked the APOE gene to late-onset Alzheimer’s. This gene has several forms. One of them, APOE ε4, seems to increase a person’s risk of getting the disease. However, carrying the APOE ε4 form of the gene does not necessarily mean that a person will develop Alzheimer’s disease, and people carrying no APOE ε4 can also develop the disease.

3.      Environmental/lifestyle factors: Research also suggests that a host of factors beyond basic genetics may play a role in the development and course of Alzheimer’s disease. There is a great deal of interest, for example, in associations between cognitive decline and vascular and metabolic conditions such as heart disease, stroke, high blood pressure, diabetes, and obesity. Understanding these relationships and testing them in clinical trials will help us understand whether reducing risk factors for these conditions may help with Alzheimer’s as well ¹⁰.

4. Plaques: These clumps of a protein called beta-amyloid may damage and destroy brain cells in several ways, including interfering with cell-to-cell communication. Although the ultimate cause of brain-cell death in Alzheimer's isn't known, the collection of beta-amyloid on the outside of brain cells is a prime suspect.
5. Tangles:Brain cells depend on an internal support and transport system to carry nutrients and other essential materials throughout their long extensions. This system requires the normal structure and functioning of a protein called tau. In Alzheimer's, threads of tau protein twist into abnormal tangles inside brain cells, leading to failure of the transport system. This failure is also strongly implicated in the decline and death of brain cells ¹¹.

Prevention: At present, there is no definitive evidence to support that any particular measure is effective in preventing AD. Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. However, epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD ¹².

Although cardiovascular risk factors, such ashypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease ¹³. The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD ¹⁴.

Symptoms:

The early symptoms of AD can include:

a)      Difficulty performing tasks that take some thought, but used to come easily, such as balancing a checkbook, playing complex games (such as bridge), and learning new information or routines.

b)      Getting lost on familiar routes.

c)      Language problems, such as trouble finding the name of familiar objects.

d)     Losing interest in things previously enjoyed, flat mood.

e)      Misplacing items ¹⁵.

As the AD becomes worse, symptoms are more obvious and interfere with your ability to take care of yourself. Symptoms can include:

a)      Change in sleep patterns, often waking up at night.

b)      Delusions, depression, agitation.

c)      Difficulty doing basic tasks, such as preparing meals, choosing proper clothing, and driving.

d)     Difficulty reading or writing.

e)      Forgetting events in your own life history.

f)       Hallucinations, arguments, striking out, and violent behavior.

g)      Using the wrong word, mispronouncing words, speaking in confusing sentences.

h) Withdrawing from social contact.

People with severe AD can no longer:

a)      Understand language.

b)      Recognize family members.

c)      Perform basic activities of daily living, such as eating, dressing, and bathing ¹⁵.

Diagnosis: Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically ¹⁶.

1.      Criteria: The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007.

These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Eight cognitive domains are most commonly impaired in AD-memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities ¹⁷.

2.      Techniques: Neuropsychological screening tests can help in the diagnosis of AD. In the tests, people are instructed to copy drawings similar to the one shown in the picture, remember words, read, and subtract serial numbers. Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia ¹⁸.

Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. It is common to perform thyroid function tests, assess B12, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), and assess levels of heavy metals (e.g. lead, mercury) and anaemia. Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment, or even the cause ¹⁹.

3. Imaging: When available as a diagnostic tool, single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination. In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes ²⁰.

Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study ²¹.

4. Non-Imaging biomarkers: Recent studies have shown that people with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to normal people. Both decreased NAA/Cr and decreased hippocampal glutamate may be an early indicator of AD ²².

Stages:

1. Stage 1: No impairment (Normal function)

The person does not experience any memory problems. An interview with a medical professional does not show any evidence of symptoms of dementia.

2. Stage 2: Very mild cognitive decline (may be normal age related changes or earliest signs of Alzheimer’s disease).

The person may feel as if he or she is having memory lapses, forgetting familiar words or location of everyday objects.  But no symptoms of dementia can be detected during medical examination or by friends, family or co- workers.

3. Stage 3: Mild cognitive decline (early stage Alzheimer’s can be diagnosed in some, but not all, individuals with these symptoms).

Friends, family and co-workers begin to notice the difficulty. During a detailed medical interview, doctors may be able to detect problems in memory or concentration.

4. Stage 4: Moderate cognitive decline (Mild or early stage Alzheimer’s disease).

At this point, a careful medical interview should be able to detect clear- cut systems in several areas:

a)      Forgetfulness of recent events.

b)      Forgetfulness about one’s own personal history.

c)      Greater difficulty performing complex tasks, such as planning dinner for guests, paying bills or managing finances.

5. Stage 5: Moderate severe cognitive decline (Moderate or mild stage Alzheimer’s disease).

Gaps in memory and thinking are noticeable, and individuals begin to need help with day-to-day activities. At this stage, those with alzheimer’s may:

a)      Be unable to recall their own address or telephone number or the high school or college from which they graduated.

b)      Become confused about where they are or what day it is

c)      Have trouble with less challenging mental arithmetic; such as counting backward from 40 by subtracting 4s or from 20 by 2s

d)     Need help choosing proper clothing for the season or the occasion.

6. Stage 6: Severe cognitive decline (Moderately severe or mild stage Alzheimer’s disease).

Memory continues to worsen, personality changes may take place and individuals need extensive help with daily activities. At this stage, individuals may:

a)      Lose awareness of recent experiences as well as of their surroundings.

b)      Tend to wander or become lost.

c)      Remember their own name but have difficulty with their personal history.

d)     Have increasingly frequent trouble controlling their bladder or bowel.

e)      Distinguish familiar and unfamiliar faces but have trouble remembering the name of a spouse.

7. Stage 7: Very severe cognitive decline (Severe or late-stage Alzheimer’s disease).

In the final stage of this disease, individuals lose the ability to respond to their environment to carry on a conversation and, eventually, to control movement. They may still say words.

At this stage, individuals need help with much of their daily personal care, including eating or using the toilet. They may also lose the ability to smile, to sit without support and to hold their hands up ²³.

  Drug Treatment:

Medicines for AD include:

• Donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne, formerly called Reminyl).
• Memantine (Namenda).

Other medicines may be needed to control aggressive, agitated, or dangerous behaviors. Examples include haloperidol, risperidone, and quetiapine. These are usually given in very low doses due to the risk of side effects including an increased risk of death.

It may be necessary to stop any medications that make confusion worse. Such medicines may include painkillers, cimetidine, central nervous system depressants, antihistamines, sleeping pills, and others. Never change or stop taking any medicines without first talking to your doctor ^[24].

TABLE 1:  SYNTHETIC DRUGS USED IN ALZHEIMER’S DISEASE

TABLE 2: HERBAL DRUGS USED IN ALZHEIMER’S DISEASE

Ayurvedic Herbs: Some Ayurvedic herbs like Guduchi, Yashtimadhuk, Padma (Nelumbo nucifera), Vacha, Convolvulus pluricaulis, Shankhpushpi, Pancha-Tikta-Ghruta Gugguli, Amalaki, Musta Arjun, Amalaki, Ashwagandha, Galo Satva, Kutaj, and others are excellent herbs for slowing down the brain cell degeneration caused by Alzheimer's. They enhance the brain's ability to function, and therefore, provide stability when used consistently ¹²⁹.

CONCLUSION: Generally, there is significant evidence supporting a role of the ACH in AD. As cholinergic function is essential for short-term memory, the cholinergic insufficiency in AD was also believed to be dependable for much of the short-term memory deficit. The management of AD remains a challenge in the modern medicine because of the pathogenesis of AD is a difficult process relating both genetic and environmental factors, therefore herbal medicines are regarded as new and promising sources of potential anti-AD drugs. Herbal medicines have prospective to treat AD because of their cognitive benefits and more significantly, their mechanisms of action with respect to the fundamental pathophysiology of the disease. Our review has acknowledged several herbal medicines with potential therapeutic effects for AD. However, no serious adverse events were reported. Moreover, the future direction should highlight the trial of new herbs that are potentially successful in treating the root of the disease.

ACKNOWLEDGEMENT: The authors are thankful to the authorities and Vice- Chancellor of Bundelkhand University Jhansi for providing support to the study and other necessary facility like internet surfing, library and other technical support to write a review article.

ABREBBIATION: Alzheimer Disease (AD), apolipoprotein E (APOE), single photon emission computed tomography  (SPECT), magnetic resonance imaging (MRI), glutamate (Glu), creatine (Cr), N-acetylaspartate (NAA), Acetylcholinesterase (AChE), nicotinic acetylcholine receptors (nAChRs), cyclic adenosine monophosphate (c-AMP), protopanaxadiol (PPD), 20(S)-protopanaxatriol (PPT), amyloid beta (Aβ), prostaglandin-E2 (PGE2), thromboxane B2 (TXB2), Amyloid beta protein (Abeta), triacylglycerol (TAG), free fatty acids (FFA), diacylglycerol (DAG), esterified sterols (STE), monoacylglycerol (MAG), Convolvulus pluricaulis (CP).

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     Agarwal P, Fatima A, Shashi Alok and Singh PP: Herbal remedies for Neurodegenerative disorder (Alzheimer's disease): A Review. Int J Pharm Sci Res 2013: 4(9); 3328-3340. doi: 10.13040/IJPSR. 0975-8232.4(9).3328-40

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