- 1 Abbreviations
- 2 Activities Relevant to the Treatment of Cognitive Disorders
- 3 Plants as a Source of Useful Therapeutic Agents in Cognitive Diseases
- 4 Plants Used in Traditional Ayurvedic Medicine
- 5 Plants Used in Traditional Chinese Medicine
- 6 Plants Used in Traditional European Medicine
- 7 Plants Used in African and South American Traditional Medicine
- 8 Conclusions
• Acetylcholinesterase inhibitors
• Alzheimer’s disease
• Traditional medicine
In traditional practices of medicine, numerous plants have been used to alleviate memory impairment both in healthy individuals and those with disease states which are now recognised as specific cognitive disorders such as Alzheimer’s disease. An ethnopharmacological approach has provided leads to identify plants and their compounds that may have potential to modulate cognitive abilities by different modes of action. A variety of therapeutic targets have been identified as relevant in the treatment of cognitive disorders, including modulation of the cholinergic system, which may be achieved by the inhibition of acetyl-cholinesterase, and neuroprotection against glutamate-induced overstimulation of N-methyl-D-aspartate (NMDA) receptors, by the use of NMDA receptor modulators. Other activities considered to be relevant in the alleviation of cognitive impairment include anti-inflammatory, antioxidant and estrogenic activities. Two of the currently licensed drugs used to treat cognitive symptoms in Alzheimer’s disease, galantamine and rivastigmine, were derived from plant sources and have been characterised as inhibitors of acetylcholinesterase. However, some plant extracts which occur as a complex mixture of components, such as Ginkgo biloba L. extract, have demonstrated relevant biological activities in relation to cognitive function, but the compounds responsible for the observed effects or the mechanisms of action have not been well characterised. Amongst the many plants reputed to enhance cognitive function in a variety of traditional medicines including Ayurvedic, Chinese, European, African and South American medicines, relatively few have been extensively studied to determine any pharmacological basis for their historical uses. Some of those plants that have generated particular interest in understanding and establishing their potential for alleviating cognitive impairment are discussed.
|AMPA||Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid|
|APP||Amyloid precursor protein|
|CNS||Central nervous system|
|mRNA||Messenger ribonucleic acid|
|NF-kB||Nuclear transcription factor kB|
|NGF||Nerve growth factor|
|NSAID||Non-steroidal anti-inflammatory drug|
|PUFA||Polyunsaturated fatty acid|
|TCM||Traditional Chinese medicine|
|TNF||Tumour necrosis factor|
|VIP||Vasoactive intestinal peptide|
Loss of memory may occur in healthy people, where it is often associated with the ageing process, or it may also occur in specific disease states in which cognitive function is impaired. Cognitive dysfunction can be a feature of a variety of disorders, including schizophrenia, multiple sclerosis, and the many pathologies associated with dementia. Dementia, which involves a deterioration of cognition, may present in patients with central nervous system (CNS) infections, Huntington’s disease, Parkinson’s disease, Lewy body disease, Pick’s disease, vascular disease and Alzheimer’s disease. Alzheimer’s disease is reported to be the most common type of dementia and is estimated to account for between 50% and 60% of dementia cases in persons over 65 years of age. There is a need for effective therapies that target loss of memory both in healthy individuals and those with specific disorders that involve cognitive impairment. At present there is a lack of therapeutic substances that can alleviate memory loss in both cases. There are many challenges involved in developing effective therapies for treating or preventing general memory loss associated with ageing and for treating or preventing the memory impairment which is a feature of the different pathologies associated with the variety of cognitive disorders such as dementia, although there may be some common therapeutic targets which may be investigated to alleviate cognitive impairment in different disease states and in general memory loss. The common symptoms of neurodegenerative diseases, such as loss of memory, have been recognised as a feature of increasing age for a long time, and it is these symptoms, rather than the specific disease states which are diagnosed in modern medicine, which have been acknowledged in many traditional practices of medicine.
Alzheimer’s disease is a progressive, neurodegenerative disease that primarily affects the elderly population and it is a major public health concern. The etiology of Alzheimer’s disease is still not fully understood. The main symptoms associated with Alzheimer’s disease involve cognitive dysfunction, which primarily involves loss of memory and recognition skills. Several other features present in the later stages of the disease, including language deficits, depression, agitation, mood disturbances and psychosis. Although the pathology of Alzheimer’s disease has not been fully elucidated, senile plaque and neurofibrillary tangle formation, and associated oxidative and inflammatory processes and neurotransmitter disturbances, occur in the CNS. In particular, a consistent neuropathological feature associated with memory loss is a deficit of acetylcholine, a neurotransmitter which is associated with cognitive function, and a cholinergic deficit has been correlated with the severity of Alzheimer’s disease.
The presynaptic synthesis of acetylcholine from choline and acetyl coenzyme A in neurons is catalysed by the enzyme choline acetyltransferase. Once synthesised, acetylcholine is stored in synaptic vesicles and is released upon neuronal stimulation into the synaptic cleft. acetylcholine may then stimulate postsynaptic receptors (or presynaptic receptors to regulate acetylcholine release) before being hydrolysed at the ester bond in the acetylcholine molecule to yield choline and acetate, under the action of the enzyme acetylcholinesterase. Thus, acetylcholine has a short half-life, and attempts to prolong its action have been investigated as a therapeutic target to restore cholinergic function in some cognitive disorders such as dementia.
Acetylcholinesterase consists of a complex protein of the α/β hydrolase-fold type having an overall ellipsoid shape containing a deep gorge about 20 A in depth. At the bottom of this gorge are four main subsites known as the ‘esteratic site’, the ‘oxyanion hole’, the ‘anionic subsite’ and the ‘acyl pocket’, and it is in this region where acetylcholine hydrolysis appears to occur, although the initial binding of acetylcholine is thought to occur at an outer region known as the ‘peripheral site’. In addition to its role in hydrolysing acetylcholine, acetylcholinesterase has also been associated with other functions including a role as an adhesion protein, a bone matrix protein, in neurite growth and in the production of amyloid fibrils, which are characteristically found in the brain tissue of Alzheimer’s disease patients, although the clinical relevance of these actions has yet to be explored more thoroughly. Another type of cholinesterase (cholinesterase) is butyrylcholinesterase, which is found mainly in serum and glia, unlike acetylcholinesterase, which is mainly distributed in neurons and erythrocytes in vertebrates. The physiological role of butyrylcholinesterase is unclear, with no endogenous natural substrate having been identified. butyrylcholinesterase is known to hydrolyse toxic esters such as cocaine, and it is considered to have a detoxifying action.
Symptoms Related to Memory Disorders in Traditional Practices of Medicine
Many disease states now known and characterised by diagnostic tests in modern orthodox ‘Western’ medicine, including cognitive disorders such as Alzheimer’s disease, were not recognised in the past as such in some more traditional practices of medicine, or may be described differently in other cultures. Consultation with traditional practitioners and healers or referral to historical literature is an unlikely approach to yield relevant information if modern medical terms are used. A more productive approach would involve searching for information according to the treatment of characteristic symptoms of a particular disease. Alzheimer’s disease is characterised by a loss of short-term and eventually long-term memory as a feature of general cognitive decline. In the later stages of the disease, language deficits, depression and agitation can occur. Therefore, investigations into traditional uses should be focused on those substances which have a reputation for improving memory or cause a general stimulation of learning processes or intellect, in whichever way it is viewed in a particular cultural context.
As well as those materials used for medicinal purposes, obtaining knowledge on the types and uses of poisonous substances may also provide some indication of their physiological effects. For example, a substance that produces symptoms of sweating, flushing of the skin and intestinal contractions may indicate that it contains compounds which stimulate cholinergic activity, perhaps by inhibiting acetylcholinesterase and thus acetylcholine hydrolysis. Compounds that may produce these effects could be of interest for study as potential cognitive enhancers.
It must also be emphasised that understanding the etiology of a disease in Western medicine may not be the same as that in other traditions. The approaches to treatment will reflect the symptoms which manifest and the recognised causes. Many African cultures include spiritual factors in the cause of disease, whilst Ayurvedic and Chinese medicine view the correction of imbalance as an aspect of the appropriate treatment. The interpretation of medical conditions described according to these traditional practices compared to the orthodox medical approach may present problems. Consequently, knowledge of the underlying pathologies which could be associated with the described and observed symptoms may be necessary to help characterise disease states.
Many plants have a reputation in a variety of traditional practices of medicine for alleviating symptoms of cognitive disorders such as memory decline; such plants have been used for medicinal purposes for a long time and in some cases continue to be used. There have been numerous scientific studies on a number of these plants to establish any pharmacological basis for their historical uses, although the extent to which each species has been investigated varies considerably. Very few of the plants that have a reputation for modifying cognitive abilities have been extensively studied, and there is frequently a lack of knowledge about the compounds responsible for the observed activities, and reliable clinical studies are also uncommon. Amongst those plants which have been subjected to more thorough investigations is Ginkgo biloba, which has shown biological activities relevant to modulation of cognitive function both in vitro and in vivo, and there is some evidence of efficacy in both healthy and Alzheimer’s disease subjects.
It is particularly interesting that of the four main currently licensed drugs (donepezil, galantamine, memantine and rivastigmine) used to treat cognitive symptoms in Alzheimer’s disease, and which have been investigated for their potential for use in other cognitive disorders, two of these (galantamine and rivastigmine) were derived from plant sources. Some of the therapeutic single chemical entities that have been developed for clinical use have arisen from toxicological investigations, very often combined with chemical modification of the active toxic compound once its structure has been determined; rivastigmine, which is based on the structure of physostigmine, is an example of this. In other cases, a compound useful in the treatment of a cognitive disorder has been discovered by studies on a plant species which has attracted interest because of its traditional use for some other purposes, such as galantamine.
It should also be considered that, although the development of new and effective ‘orthodox’ drugs as single chemical entities for some cognitive disorders is one aim, the use of plant extracts can still be valuable, particularly as in many cases more than one constituent in a plant is responsible for the overall effect, and it is too simplistic to conceive that a single compound has the same effect or efficacy. Herbal preparations consisting of complex mixtures for therapeutic purposes are generally not accepted in modern Western medicine, and consequently many potentially useful plants will not be accepted for clinical use, although they may be extensively used in complementary and alternative therapies. In these circumstances, the role of scientific research is to provide evidence for their therapeutic applications in conventional Western medicine and to identify compounds responsible for the activity so that herbal products with the appropriate qualitative and quantitative chemical profile can be made available, with greater assurance of safety and efficacy. In addition to concerns regarding the quality control issues associated with herbal medicinal products, the potential for their interactions with other medicines has not been widely studied and these issues need to be addressed.
In conclusion, it is apparent that the pharmacological activities of plants and their compounds often appear to reflect their uses in traditional medicine, although traditional medicines used to treat other disorders and poisons can also provide leads to develop herbal medicines and drugs to alleviate symptoms in cognitive disorders.