Novel Leads from Herbal Drugs for Neurodegenerative Diseases

The Parkinson's-Reversing Breakthrough

Natural Remedies for Parkinson Disease

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Maheep Bhatnagar

Abstract This article summarizes the salient features of new therapeutic leads from herbal sources for various types of neurodegenerative diseases. Efforts made in using existing knowledge on several popular medicinal plants, particularly those utilized in the Indian traditional medicinal and Ayurvedic system discussed in light of recent research. A few promising plants such as Asparagus racemosus, Bacopa monnieri, Centella asiatica, and Mucuna pruriens are worth exploring for drug development for neuroprotection.

Keywords Medicinal plants, Neurodegeneration, Neuroprotection, Neurodegener-ative diseases

14.1 Introduction

Herbal medicines are being used by about 80% of the world's population, primarily in the developing countries, for primary healthcare, because of its better cultural acceptability, better compatibility with the human body, and lesser side effects. According to the World Health Organization's (WHO) definition traditional medicine comprises therapeutic practices that have been in existence, often for hundreds of years, before the development and spread of modern systems of medicine and are still in use. Herbal drugs constitute only those traditional medicines that primarily use medicinal plant preparations for therapy. The earliest recorded evidence of their use in Indian, Chinese, Egyptian, Greek, Roman, and Syrian texts, dates back about 5000 years ago. However, the last few years have witnessed a significant increase in their use in the developed world. India, China, and other neighboring countries have well founded traditional systems of medicines where plant based therapeutic agents occupy an important niche in health management.

Animal Biotechnology and Neuroscience Laboratory, Department of Zoology, M.L. Sukhadia University, Udaipur-313001, India e-mail: [email protected], [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4.14, © Springer-Verlag Berlin Heidelberg 2009

The traditional use of herbal preparations existed in Indian medicinal systems long before their usefulness was accepted in modern scientific approaches to healthcare. Even today in the majority of rural and urban areas in India, as well as in several other parts of world, traditional herbal health-care is practiced. According to one estimate, herbal products now constitute a major portion -20% of international pharmaceutical industry. About 1500 to 1800 products are sold in US markets alone [1].

Although a large number of scientific studies have been conducted in India and world wide on medicinal plants, traditionally proven herbal preparations/formulations do not yet fully conform to standards of drug testing, safety, and efficacy. Though opportunities for developing traditional preparations as drugs with international acceptance are enormous, there is hardly any intensive effort in this direction at the government or industry level in India, which has resulted in a decline in enthusiasm for studying plant preparations for their therapeutic value. But one has to believe that approx 25,000 living plant species in India contain a much greater diversity of bioactive compounds than any chemical library made by man. Although it is also true that extracts prepared from medicinal plants contain a variety of molecules with potent biological activities, unfortunately, it is often difficult to analyze their biological activities because of their complex nature and possible synergistic actions [2, 3].

14.2 Ayurveda, Herbal Drugs, and the Central Nervous System

Plant products or plant parts are the main source of medicines in Ayurveda, where they are either used as extracts or decoctions. Charak Samhita (900 BC) is the first recorded treatise of the Ayurveda. It consists of eight sections with descriptions of more than 341 Indian plants useful as medicines. In Ayurveda, the drugs that act on the central nervous system CNS are broadly classified into ten categories (Table. 14.1).

Table 14.1 Ayurvedic classification

1. Medya (Intelligence and memory)

2. Samjnasthapa (Resuscitative)

3. Madakari (Narcotic)

4. Nidrajanana (Hypnotic/sedative)

5. Vedanastrhapana (Analgesic)

6. Apasmarahara (Antiepileptic)

7. Unmadhara(Anti-insanity)

8. Jawarahara (Antipyretic)

9. Chardi (Anti-emetic)

10.Vamnopza (Emetic)

The medhya in Ayurveda refers to all substances that promote or are beneficial for medha (intellect), dhriti (concentration), and retention and smiriti (memory). In modern pharmacology, these substances are called nootropic agents. A number of Ayurvedic drugs are grouped as rasayanas (rejuvenators). According to Ayurvedic physicians, rasayanas increase the life span and delay ageing by counteracting the degenerative changes associated with ageing. Modern medicines have also recognized the rasayana group of drugs as antistress/adaptogens and could be useful in treating various CNS disorders.

Ayurvedic drugs are also garnering much attention for diseases with no or inadequate drugs for treatment in modern medicine, such as metabolic and degenerative disorders. Most of these diseases have multifactorial causation, and there is a growing realization that in such conditions, a combination of drugs acting at a number of targets simultaneously is likely to be more effective than drugs acting at one target; the one target, one drug paradigm is not likely to be satisfactory in such cases. Ayurvedic drugs, which are most often multi component have a special relevance for such conditions, and are attracting much attention. No doubt this would require a detailed study to obtain a proof of the concept, but these are the opportunities offered [2].

The multi target approach is the basic doctrine of Ayurveda, which takes a holistic view of the human system. In therapeutic terms, it implies that the treatment of disease should not be directed to a single tissue or organ but to the body system as a whole, taking into consideration the interconnectivity of the various bodily organs and their mutual dependence. For various reasons Ayurveda has not been exposed much to modern scientific study. Investigations of the biological activity of multi component Ayurvedic drugs will also bring Ayurveda into the main stream of scientific research. Encouraging research and development studies will help to develop a much needed interface between Ayurveda and modern medicine, and may further confirm how best the two might complement each other [2, 3].

India has a well recorded and well practiced knowledge of traditional herbal medicine, but, unlike China, it has not been able to capitalize on this herbal wealth by promoting its use in the developed world, despite the later's renewed interest in herbal medicine. Disseminating knowledge of traditional system of medicine can be achieved by judicious product identification based on diseases that have no medicine or only palliative therapy. Ayurvedic masters had thus developed certain dietary and therapeutic measures to arrest/delay ageing and rejuvenating the whole functional dynamics of the bodily organs. This revitalization and rejuvenation is known as the 'Rasayana chikitsa" (rejuvenation therapy). "Rasayana chikitsa" is not only a drug therapy, but a specialized discipline of Ayurveda that deals mainly with the preservation and promotion of health by revitalizing the metabolism and enhancing immunity. "Rasayana" therapy is done for a particular period of time with a strict regimen of diet and excercise. "Rasayana" drugs are rich in antioxidants, and are good hep-atoprotectents and immunomodulators. Shushruta (an ancient Ayurvedic surgeon), in defining "rasayana" therapy, said that it arrests ageing (Vayasthapam) and increases life expectancy (Ayushkaram), intelligence (Medha), and strength (Bala), thereby enabling one to avoid diseases.

There has been much research on the plants used as "Rasyana drugs" in order to understand them in the modern context. Puri [4-7] gave an account of the herbs used in various rasayana preparations, while Udupa [8] studied the effects of rasayana drugs on psychosomatic stress. Rasyana drugs have been proven effective in the treatment of epilepsy [9], convulsive disorders, reduction of anxiety and apprehension, and in calming the mind [10].

14.3 Neurodegenerative Diseases:

Unlike other categories of diseases, such as infections or trauma, neurodegenerative diseases share a common etiology or some clinicopathological features. There are two major common features of the degenerative diseases:

1. They are diseases of neurons, which selectively affect one or more functional systems of neurons. For example, there is selective degeneration of striatonigral dopaminergic neurons.

2. They are marked generally by symmetric and progressive involvement of the central nervous system.

These diseases also differ among themselves quite distinctively. Some of them have a heritable pattern, while others are sporadic. Some show atrophy or loss of affected neurons, with or without specific features. Thus, specific diagnosis of such diseases can be made only by correlating the clinical as well as pathological findings. For a better understanding, these diseases are grouped according to the part or parts of the brain that are principally involved (Table. 14.2).

Table 14.2 Neurodegenerative diseases and areas of brain affected

Disease

Alzheimer's disease (AD) Pick's disease

Huntingdon's disease Idiopathic Parkinson's disease Post encephalitic Parkinson's Striatonigral degeneration Progressive supranuclear palsy

Shy-Drager syndrome Olivopontocerebellar degeneration Friedreich's ataxia Ataxia telengiectasia

Amyotropic lateral sclerosis Werding Hoffman disease Kugelberg welander Syndrome

Affected area of brain Basal ganglia and brain stem

Basal ganglia and brain stem

Spinocerebeller area Motor neurons

Alzheimer's disease (AD) is the most common disease of aged persons [10]; its onset is rare before the age of 50. The most frequent and initial complaints are impairment of concentration, memory, and other higher intellectual functions. Over the course of 5 to 10 years, progressive memory loss, disorientation, and language dysfunction often leads to a mute, immovable state. Death usually results from infections. Although 10% of cases appear to be clearly inherited, most are sporadic. Pathologically, the disease is characterized by a widening of the cerebral sulci. Microscopic features include the presence of neurofibrillary tangles and senile plaques. Senile plaques are found most frequently in the cerebral cortex and limbic structures. They range from 20 to 150 |m in diameter, are composed of focal collections of dilated, tortuous neuritis that often contain neurofibrillary tangles arranged around a central amygdaloid core. This Congo red positive core is composed of a P-amyloid protein. In addition to these two characteristics, AD is also characterized by a deficiency of acetylcholine and, the enzymes acetylcholinesterase (AchE) and choline acetyltransferase (ChAT), in the cerebral cortex, hippocampus, and amygdala. The gene responsible for the P-APP protein is located on chromosome 21 [11, 12].

Huntington's disease (HDD) usually appears between the ages of 20 and 50 years. It is characterized by extrapyramidal movements combined with progressive dementia. It is an autosomal dominant condition. Those who inherit it from their fathers usually manifest it much earlier in life than those who inherit it from their mothers. The defective gene is assigned to chromosome 4. In HDD, the brain is comparatively small (less than 1000 g) and demonstrate marked atrophy in Caudate and Putman, with conspicuous dilatation of the frontal poles of the lateral ventricles. There may be secondary atrophy of the cortex and Globus pallidus. Microscopically, there is severe loss of both large and small neurons in the dorsal region of these nuclei. There is also marked fibrillary gliosis.

Parkinson's is known as a disturbance of motor function, characterized by an expressionless face, slow voluntary movements, and progressively shortened accelerated step, rigidity, and, in most cases, characteristic tremors. Such motor disturbances are seen in a number of other diseases, that show damage to the nigrostriatal dopaminergic system. The disease may be developed as a result of use of dopamine antagonists, toxins, pesticides, stress etc. Ideopathic Parkinson's or paralysis agitans is a sporadic, progressive disorder and is the most common form of the disease. The onset age of the disease is 50 to 80 years. Broadly speaking the disease shows depigmentation of the substantia nigra and locus coeruleus. Microscopically, there is a loss of melanin containing neurons from these regions, with extraneuronal pigment deposition, and the presence of lewy bodies in the remaining neurons. Lewy bodies are intra cytoplasmic, eosinophillic, round, or elongated inclusions that consist of a dense core surrounded by a paler rim. The loss of the dopamine containing neurons from the substantia nigra results in dopaminergic depletion in the striatum, because this is the principal site of their axonal projections. The severity of the Parkinson's syndrome is proportional to the severity of the dopaminergic deficiency. This deficiency can be compensated at least in part by replacement therapy with L-dopa [12].

Motor neuron disease (Amyotrophic lateral sclerosis) is characterized by neuronal degeneration, concentrated mainly in the upper and lower motor neurons of the pyramidal motor system. The upper motor neurons are in the motor cortex and their axons traverse the internal capsule and corticospinal tract to synapse on the lower motor neurons in the cranial motor nerve nuclei and the motor neurons in the anterior horn of the spinal cord. Pathologically, degeneration of the upper motor neurons produces axonal loss and atrophy of the corticospinal tracts in the lateral columns of the spinal cord. The neurological symptoms exhibited by patients include spasticity, hyperflexia, muscle atrophy and weakness. The disease is also sporadic in most cases, but an approximately 2:1 male predominance has been noted. Onset is typically in late middle age, with usually fatal outcome in 2 to 6 years. There is no known treatment [12].

Increased generation of oxidative free radicals or an impaired antioxidant defense mechanism has been identified in the ageing process and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, and in chronic stress induced perturbed state [13, 14]. Major oxidative free radical scavenging enzymes are superoxide dismutase, catalase, and glutathione peroxidase. Deficient functioning of these enzymes leads to an accumulation of toxic oxidative free radicals and consequent degenerative changes. Potential antioxidant therapies for CNS disorders should therefore include either natural antioxidant enzymes or agents that are capable of augmenting the function of these oxidative free radicals scavenging enzymes [15]. By virtue of their proposed properties and clinical uses, rasayana may provide potential intervention against oxidative threats, both in healthy and diseased states [16]. Bhattacharya et al. [17] have shown that the active principle of Withania somnifera increased cortical and striatal concentrations of antioxidant enzymes. Jain et al. [14] and Shukla et al. [18] also reported the effects of Semi-carpus anacardium and W. somnifera on SOD, CAT, GPX, and LPO and demonstrated a significant increase in SOD and decrease in LPO. Panda and Kar [19] investigated the effects of W. somnifera root powder, administered for 15 and 30 days, and demonstrated a significant decrease in LPO and increase in both SOD and CAT.

14.4 Medicinal Plants, Neurodegenerative Diseases, and Therapeutics:

According to a WHO report (2001), approx 450 million people suffer from mental or behavioral disorders, yet only a small fraction of them receive even the most basic treatment. This amounts to 12.3% of the global burden of disease, which may increase to 15% by 2020. It is now becoming exceedingly apparent that the available psychotherapeutics does not properly meet the therapeutic demands of the vast majority of patients with mental health problems, and that herbal remedies remain the ultimate therapeutic hope for many such patients in the world. Critical analysis of our current understanding of the most popular and well studied CNS active medicinal plants reveals that many therapy related questions have not yet been properly investigated.

Drugs having CNS activity are widely used around the world. Mostly these are synthetic in nature, which are expensive, and with numerous side effects. In a systematic analysis published in 1997, it was reported that 157 of 520 drugs (30%) approved by the Food and Drug Administration (FDA) in the USA for the 11years period between 1983-1994, were natural products or their derivatives [20]. This report revealed in addition, that when focused efforts were made to discover natural products for clinical use, the success level rose dramatically. Thus, during the same period, 61% of anticancer agents approved were natural products or their derivatives. In the absence of targeted programs for natural products, there was no success. There were no analgesics, antidepressants, anxiolytics, or other CNS active drugs derived from natural products that were approved during the 11 year time period analyzed.

The situation has not changed much in recent years. Although identification of hits and leads from secondary plant metabolites continues to be a major goal of many drug discovery projects, most of the efforts do not concentrate on the search for agents potentially useful for the treatment of CNS disorders. In addition, comparatively few reports on the neuronal function modulating activities of herbal extracts and their active constituents appear regularly in various journals. So there is a dire need for a concentrated effort to define and understand the most appropriate therapeutic plants or to exploit them for identifying and developing CNS active drugs. On the other hand, it is worth noting that in India, a number of plants are available that show remarkable CNS activity, but to date, no systematic or scientific study has been carried out on such plants. In the past, several medicinal plants were identified for their effects on CNS. Satyavati [21] and Dhawan [22, 23] published a comprehensive list of various Indian plants with proven CNS activity. Properties of some of these plants are summarized in Table. 14.3.

At present, in modern medicine, therapies for many CNS diseases are not available. Drugs available for the treatments of anxiety, depression, and mental health conditions are not satisfactory, as the majority of them are of synthetic origin or derived from synthetic molecules. Chlorpromazine, reserpine, tricyclic and MAO depressants, benzodiazines, meprobamate, etc., used for the treatment of psychi-actric patients; bicuculline, pentylenetetrazol, amphetamine, methylphenidates, etc., for CNS stimulation; barbiturates, hydantoin, oxazolidone, succinimides, and acetyl urea as antileptics; bromocriptine, apomorphine, levodopa, amatidine, trihex-iphenydryl, and procyclidines for the treatment of Parkinsons's, are some of the drugs that have severe side effects and lead to dependency development.

Herbal remedies for such conditions have been known since time immemorial, and efforts made during the past few decades reconfirm that several herbs are indeed therapeutically useful for the treatment of various CNS disorders. Although all the active principles and mode of action of these herbal drugs/ formulations have not yet been precisely defined, but available data indicate that they could be useful sources to develop better, effective, safer, and cheaper drugs with novel modes of action. In the past few years, the number of reports on well-planned clinical trials using

Table 14.3 Composition of certain formulations in practice for treatment of CNS disorders

Name of formulation and its composition

Therapeutic implications

Mentat

Hyocyamus reticulate Mucuna pruriens Sida cordifolia Withania somnifera Trasina

Banisteria cappi Claviceps purpurea Datura stramonium Mucuna pruriens Viciafaba BR-16A

Acorus calamus Bacopa monnieri Celestrus peiniculatus Centella asiatica Evolvulus alsenoides Mukta pisthi

Nardostachys jatamanasi Orchis mascula Prunus amygadalus Syzygium aromaticum Valarana wallachii Withania somnifera Zinziber officianalis

Galanthamine

Galanthus warnori

EGB761

Ginkgo biloba

Brain vita

B. monnieri extract

Swiss Ginkgo biloba

Anti-Parkinson's

Anti-Alzheimer's

Anti-Parkinson's

Anti-Alzheimer's

Dementia, dementia of Alzheimer's type, and multi-infarct dementia Cognitive functions

Cognitive functions standardized herbal extracts has increased. No doubt, the consequences of these efforts will result in standardized herbal formulations acceptable to both patients and industry. A brief account of the potential herbs of Indian origin and those that are not native to India with therapeutic leads for the treatment of various CNS diseases including neurodegenerative disorders is presented below.

14.5 Plants Native to India

14.5.1 Acorus calamus

Acorus calamus, known as vacha in Ayurveda, is an aromatic marsh herb cultivated throughout India. Its medicinally useful part is its rhizome. Its essential oil consists of a range of sesquiterpene hydrocarbons, alcohols, and ketons (e.g., acorone, acoragermacrone, calamendiol) as well as eugenol, methyl isoeugenol, and phenyl propane derivatives a- and P-asaron. In Ayurveda, vacha has been acclaimed as a treatment for epilepsy and as a tranquilizer, in addition its action on bronchial diseases, indigestion, etc. The juice of the herb is also recommended in Sushruta Samhita for intellectual vigour and longevity. The ethanolic extract of the rhizome has been shown to possess neuroprotective action in acrylamide-disabled rats [24].

14.5.2 Asparagus racemosus

This is a tall, highly branched scandent under shrub, found growing wild in almost all parts of India and also in the Himalayas up to an elevation of 1500 m. It is widespread in upper Gangetic planes, especially in Bihar, where it comes up profusely after rains. Its medicinally useful part is the root, which contains glycosides (4%), as well as free sugar and oligosaccharides. The roots have been shown to contain, in addition to the ubiquitous sitosterol, undecanyl cetanoate, 4, 6-dihydroxy-2-o-(2'hydroxyisobutyl) benzaldehyde, flavonoids and pyrrolizidine alkaloid, and as-paragamine A [25]. An extract was shown to possess a potent antioxidant property and was evaluated against kainic acid induced hippocampal and striatal neuronal damage in anesthetized mice. The extract supplemented mice showed reduced lipid peroxidation and an increase in glutathione peroxidase and glutathione contents, thus demonstrating its antioxidant activity [26, 27]. Recent studies have demonstrated the neuroprotective effects of asparagus root extract in an in vivo model of aluminum and paraquat induced neurodegeneration [28, 29].

14.5.3 Bacopa monnieri

This plant is commonly found in wet marshy and damp places throughout India. It is a succulent, creeping herb with a stem 10 to 20 cm long that produces roots at nodes. The drug contains alkaloid (brahmine) and triterpenoid saponins (bacosides A and B) [30, 31]. The plant is used as a nervine tonic, and diuretic and is commonly used to treat asthma, epilepsy, insanity, and hoarseness. It is a major constituent of medhya rasayana formulations, which facilitates learning and improves memory [32-37]. Initial studies using 50% ethanolic extract of the whole plant without roots demonstrated its effects on short and long term memory retention. Bhat-tacharya and his coworkers [38] studied the effects of B. monnieri extract on AD using a rat model. Oral administration of a 5 to 10 mg extract per kilogram of body weight markedly reduced the memory deficits as well as acetylcholine concentrations, choline acetylase activity, and muscuranic receptor binding in the hippocampus and frontal cortex [38].

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