Herbal Approaches for Alzheimer Disease: A Review

"Plague of the Twenty-First Century," or “Alzheimer disease” is anneuro-degenerative disease that influenced the world's elderly population. The prevalence of Alzheimer's disease is expected to increase to one hundred thirty-five million by 2050, with no treatment(s) currently available to cure or monitor the disease's progression. The current treatment(s) have lesscapability to manage symptoms or delay disease development, and they can cause serious side effects. The cost of overall treatment is high for both the patients and their caregivers or family members. As an example, there is an serious requirement to find safer alternative treatments for better management of Alzheimer's disease. The various Indian herbal medicines such as Centella asiatica,Celastruspaniculatus Curcuma longa, Clitoriaternatea,Bacopa monnieri, Withania somnifera, has been reviewed in this article. Eclipta alba, Desmodiumgangeticum, Evolvulusalsinoides, Moringa oleifera, and Convolvulus pluricaulis are among the plants that have shown promising effect in the treatment related to cognitive disability.


INTRODUCTION
A germen psychiatrist in 1906, and neuropathologist (Alois Alzheimer), first identify the neurodegenerative disease, Alzheimer's disease [1]. It causes a person's intellect and memory to deteriorate, eventually leading to the loss of their ability to carry out day-to-day tasks

Review Article
independently. It is the most prevalent form of dementia, accounting for 60-70% of cases [2]. The onset of the disease is associated with ageing and is seldom found in the people of young age [3]. It is generally seen in people around the age of 65 or more.Currently, there is no treatment for Alzheimer's disease, which is considered the "Plague of the Twenty-First Century" since the number of cases is probable to rise from 48 million to 135 million by 2050 [4]. To successfully control and minimise the disease's proliferation, it is essential to find a cure or successful methods of prevention.
Alzheimer disease result in neuronal damage and death due to the disruption of some essential process as communication in neurons and with brain cells, repair, and regeneration and metabolism. In most cases, the condition gets worst with the increase in age. In the early phase, memory-related neurons in the allocortex area of brain and hippocampus are lost. After this stage this disease progresses to the next stages, affecting regions of the cerebral cortex responsible for thought, language, and social behaviour. This is a fatal disorder which also spreads to the other part of the brain, eventually make the patient unable to function and live independently which leads to death.

Molecular Mechanisms of Alzheimer
1. Oxidative stress:This term describes a condition in which the Oxidative stress in the body is caused by ROS (reactive oxygen species), which is particularly prevalent in disorders related to age likeAD. Inearly phase's ofAD, oxidative damage develops in the brain. It has an effect well before plaque pathology begins, as it occurs before amyloid-beta(Abeta) deposition and formation of intracellular neuro-fibrillary tau protein tangles are irregular. Reactive Oxygen Species play a role in neuronal death at the cellular and tissue levels and neurodegenerative processes [5]. 2. Occurrence of Aβ plaques: The degradation of the AβPP results in the formation of A β proteins. These proteins start to stick together and lead to formation of plaques between neurons at abnormally high levels. Cellular function is eventually disturbed as a result of these aggregates [6].

Neurofibrillary tangles formation:
When abnormally high levels of hyperphosphorylated tau protein build up within the neurons, neurofibrillary tangles form. In healthy neurons, the tau protein is important for attaching to and stabilising microtubules. [7]. after tau detaches from microtubules, it links to other tau molecules and creates threads that connect to form tangles, which impair synaptic connection between neurons in AD [8]. The cleavage of a reversing barrier at the axon beginning section causes tau proteins in the axonal area of neurons to be missorted to the somato-dendritic section [9]. 4. Microglial cells: Microglial cells act as brain macrophages, removing cell debris such as Aβplaques, harmful chemical and damaged neurons. Furthermore, astrocytes help remove cell debris and plaques from the brain. In AD, these brain microglial cells gather around the neurons but are unable to fulfil their role of clearing debris. As a result of their accumulation, chemicals are released into the brain, causing chronic inflammation [10]. 5. Vascular causes: Alzheimer disease can also lead to A build-up of plaque in the brain's arteries, as well as artery hardening (atherosclerosis), ministrokes, and other conditions [11], may retard flow of the blood and oxygen supply of oxygen to the brain and results in a degeneration and complicated loop i.e. a cause and consequence of Alzheimer's disease [12]. 6. Brain atrophy: In AD, neurons are damaged and die. As a result, the neural network can break down, cause shrink in brain size [13].
The hippocampus of the medial temporal lobe, which is predominantly engaged in memory and emotion, suffers from the loss of brain function. The deterioration then accelerates impactingbrain glucose metabolism and cause a decrease in neuronal processing in the parietal and temporal lobes on both sides [14]. The parietal lobe controls, self-awareness, memory retrieval, attention, sensation, and theory of mind [15][16][17]. The temporal lobe is involved in episodic memory, feelings, and mood [18]. As a result, memory, emotion, and perceptual control are all controlled by the brain regions afflicted by Alzheimer's disease.

Treatments Available Currently for Alzheimer's Disease
Currently only few medications are available to cure Alzheimer's disease, and most of them cantreat the symptoms only. Symptoms such as memory loss, on the other hand, are slowed, extending life and improving quality of life for those who are affected. Donepezil, rivastigmine, and galantamine are some of the drugs that are used to treat mild to severe Alzheimer's disease. These cholinesterase inhibitors, which stops acetylcholine from being broken down found essential for memory and learning. Memantine is an NMDA antagonist that is used to treat AD [19]. Memantine and donepezil is used for this in combination. Depression, rage, restlessness, and anxiety are all indications of AD, and other drugs are used to treat them. Among these are imipramine, mirtazapine, bupropion, citalopram, sertraline and duloxetine.

Alternative Therapies
As the world's population grows and people live longer, AD cases are on increasing all over the world. According to report conducted by WHO on dementia reveals that around 50 million peoplethroughout the nation are suffering from dementia and every year new cases of 10 million are cont. adding to this no.which reflects that a person worldwide developing dementia in every three sec [21].This fastonset of ADrequires the advancement of new prevention and treatment methods for Alzheimer's disease.The new therapies are ineffective, have a high number of adverse effects, and suffer from low patient cooperation. These therapies are also costly for patients and providers, as thecosts of continuingpresence and hospital expensesregularly increasing year after year [22]. This necessitates the introduction of safer alternative of therapies that are being used as anti-AD therapies since ancient times and have been shown to be efficient. Ayurveda, traditional Chinese rituals, meditation, and exercise are all examples of such therapies. Many therapies focused at healing function of synapses and memory has shown to be helpful in reducing the progression of Alzheimer disease and increase effect ofcurrent therapy.

Herbal Drugs
Ayurveda, a Sanskrit term that means "scripture of immortality," is the philosophy of life and health that promotes a holistic approach to care to keep the body, mind, and soul in balance. The 5 fundamental tatva of the universe: fire, space, air, earth and water [23] are the foundations of this traditional medication system. Its roots can be found in India's Indus Valley Civilization and the Indian subcontinent (about 3,000 BC).
Several herbal medicines that has been used to treat neuro-degenerative diseases all over the world. Dor example Salvia officinalisand Salvia lavandulaefoliaare used in European regions to improve memory since 16th century [24] and found to be affected with the help of different clinical trials [25,26]. The Ayurvedic tradition has long used Bacopa monniera (water hyssop) to aid memory and cognitive abilities. The rejuvenative tonic Withania somnifera root is also mentioned inTraditional Books like Ayurveda for the congnition improvent. [27][28][29][30]. various traditional remedies are attaining popularity as a result of their perceived efficacy, protection, and affordability. Indeed, experimental studies have only recently begun to provide indication and justification of choosing herbal therapy in cognitive disabilities.

Biological Source
Bacopa monnieri (B. monniera) is a minor, ever growing creeping herb with a number of branches,leaves are oblong, and flowers can beslight purple or can also be white belonging to Scrophulariaceae.In India it is popularly known as Brahmi and can be used for its revitalisingand nootropic properties;it also improves cognition power and intellectual abilities. Italso has been utilised to cure a range of diseases by practitioners of India's traditional medicine for thousands of years.

Chemical Constituent
Bacosides, which are triterpenoid saponins, are the most important chemical constituents of B. monniera. This plant also contains the alkaloids brahmine, nicotine, and herpestine. Bacopasides I-XII, which are new saponins, have also been discovered.

Effect of Brahmi in AD
According to a study on olfactory bulbectomized mice by Le et al., this plant helps in by protecting cholinergic nerve cells in the medial septal nucleus that extend inhippocampus of our brain. A rat model of Alzheimer's disease showed that alcoholic Brahmi extracts inhibited cholinergic neuron degeneration, implying that the medication could be used therapeutically. According to these findings, the plant extracts have a cholinergic effect comparable to existing therapies such as donepezil, rivastigmine, and galantamine [37,38]. The plant extract diminishthe deposition of Aβ and hippocampus damage due to stress and signalling potential therapeutic effect in Alzheimer's disease [39,40].

Biological Source
Centella asiatica, an annual plant, belonging toApiceae that is also known as jalbrahmi ormandukparni, is found throughout India. It bears small oval fruit and possess green leaves with fan like shape and the flowers are white or light purple and can also be pink [41].
The Ayurvedic method of medicine has used the leaves of mandukparni as a memory enhancer [42]. Its use has also been recorded in traditional Chinese medicine and the African medical system. It's used to slow down the ageing process, avoid memory problems, and improve memory when combined with milk [43].

Biological Source
Withania somnifera (W. somnifera) is a small woody shrub that belongs to the Solanaceae family and is widely cultivated in India. The herb is also known as Indian ginseng, winter cherry, or ashwagandha. It has greenish or yellowish flowers that are about a centimetre long [51,52].

Effect of Ashwagandha in AD
The roots helps in the suppression of the nuclear factor (NF-B), and regulates the expression of genes involved in inflammatory mediators and oxidative stress parameters and thereby producing anti-inflammatory and antioxidative effect by preventing the development of A β. It helps in the regeneration of synaptic function and the decrease apoptosis. It encourages nuclear factor related to E2-related factor 2 (Nrf2) to migrate to the nucleus, resulting in an increase in antioxidant enzyme expression and neuroprotective proteins like haeme oxygenase-1, demonstrating antioxidant effects that are beneficial in the treatment and prevention of AD [57,58].

Biological Source
Curcuma longa (C. longa) Linn also known as turmeric, is a perennial plant in the Zingiberaceae family. It is derived from the plant's rhizome and is widely used as a food flavouring and colouring agent in India. In South and Southeast Asia, it is grown for commercial purposes. [59][60][61].

Effect of Turmeric in AD
Curcumin has anti-inflammatory properties by inhibiting the development of TNF-α, IL-1β, and further pro-inflammatory cytokines in astrocytes and microglia, such as IL-8, MIP1β, and MCP-1. By modifying the Nrf2-Keap1 (Kelch-like ECHassociated protein 1) pathway, the oxidative damage is reduced and improves functions that are cognitive, particularly in the case of ageing. By modulating the Nrf2-Keap1 (Kelch-like ECHassociated protein 1) pathway, it reduces oxidative damage and improves cognitive function, particularly in the case of ageing [64]. When curcumin binds to Keap1, Nrf2 attaches to Keap1 and present in the cytoplasm is released.
A study found that daily curry eaters beat those who had never or only sometimes eaten it on a typical Montreal Cognitive Assessment(Mini-Mental State Examination, MMSE) [65]. It can also limit microglia development, lower the level of cholesterol, inhibit AChE, modulate the signalling pathway of insulin, prevent brain dysregulation induced by bio-metal poisoning, and inhibit acetylcholinesterase [66,67]. The extensive consumption of turmeric in the Indian population has also been linked to lower rates of AD, implying a neuroprotective effect for haldi [68]. It is also used in food preparation and is completely healthy,along with the exception of diarrhoea, nausea, dizziness, or stomach upset if eaten in large amounts.

Biological Source
Convolvulus pluricaulis is a species of Convolvulus (C. pluricaulis) Choisy is a perennial, wild, prostrate herb that is innate to Northern India and belongs to the Convulvulaceae family. In the ancient system of medicine, it also known as shankhpushpi and have activity as a tonic to boost memory and brainpower [69].

Effect of Shankhpushpi in AD
Its aqueous extracts protect a Drosophila model of AD against early mortality by neutralising human microtubule-associated tau protein mediated neurotoxicity. The tau protein in tauopathy is greatly reduced by Shankhpushpi extracts. increases antioxidant enzyme activity and reduces oxidative-stress mediated by tau protein [75]. The ethanolic extracts of Shankhpushpi increase neurite outgrowth, which improves memory [76]. The action of C.pluricaulis can be triggered by adding it to daily food. Its small leaves, flowers, and roots, as well as the paste produced from them, can be eaten on a regular basis. Fig. 19.leaves of drumstick tree

Biological Source
Moringa oleifera (M. oleifera), a member from the Moringaceae family, is the utmost widely distributed plant. It's commonly referred to as a drumstick. This plant is instinctive to India, and trees can grow up to height of 10 metres in length.

Chemical Constituents
It contains Vitamins i.e.vitamin A and C, alkaloids, isothiocyanates, tannins, and saponins and polyphenols i.e. flavonoids, chlorogenic acid,glucosinolates, and phenolic acids are the main chemical constituents in M. oleifera [77].

Effect of Drumstick tree in ADS
It reversed the effects of colchicine on NE, 5-HT, and DA levels in the brain. Its antioxidant effect has been linked to improvements in learning and memory. Other studies have also shown that M. oleifera protects in contrast to memory loss in laboratory models for dementia.

CONCLUSION
Alternative medicine is used in the treatment of Alzheimer's disease from ancient times, and many extractions of medicinal plants and herbal formulae showed potential. Medicinal plants provide fertile ground for novel drug development due to the availability of diverse chemical ingredients and their capacity to work on a different type of biological targets. The no. of persons suffering by age-related diseases such as Alzheimer's disease will substantially increase as the world's population grows. The number of AD cases is expected to increase to 135 Million by 2050 in the ageing population. As a result, advanced research and development of effective preventive and therapeutic methods are gaining increasing interest.This paper has mentioned some of herbs related to the AD and their effect. However, more work is still needed in order to convert this potential into actual treatment. Multicentre clinical trials should be done to confirm the effectiveness of the herbal medications alone or in the form of formulations for the treatment of AD.

NOTE
The study highlights the efficacy of "Ayurveda " which is an ancient tradition, used in some parts of India. This ancient concept should be carefully evaluated in the light of modern medical science and can be utilized partially if found suitable.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.