Direct cholinergic receptor stimulation has been explored as one therapeutic target to enhance cognitive function. Cholinergic agonists are reported to facilitate learning and memory, but cholinergic antagonists impair learning and memory [20, 21]; thus cholinergic agonists may be useful in cognitive disorders. Direct stimulation of the M1 muscarinic receptor with agonists such as xanomeline (2), which is an analogue of the natural compound arecoline, is reported to improve cognition both in animal models and in AD patients, and antagonists of central presynaptic M2 receptors, which include analogues of the naturally derived himbacine (3), also enhance cognitive ability by increasing the release of ACh (1) . To date, treatment with compounds that directly interact with muscarinic receptors has not been a major approach to alleviate cognitive disorders such as AD, perhaps due to the unpleasant cholinergic side-effects such as gastrointestinal contraction and sweating, reported to be associated with muscarinic receptor modulators.
15.2.3 Nicotinic Receptor Stimulation/Nicotinic Agonists
Behavioural studies have shown that nicotinic receptors participate in cognitive functions . Nicotinic receptors are reduced in cortical brain areas in AD [24-28], and nicotine (4) upregulates nicotinic receptors and increases ACh (1) release [29-31]. Nicotine treatment in various in vivo studies, including administration to rats with cholinergic brain lesions and in aged monkeys, has been shown to improve cognitive function [32, 34].
Thus, nicotinic agonists may enhance cholinergic neurotransmission and therefore cognitive function in some disorders that feature memory impairment. In support of this, some studies suggest smoking may protect against AD development, and administration of nicotine to AD patients and to healthy (non-AD) elderly people improved cognitive function [35-39]. However, some cohort studies have shown that smoking shows either no association with AD risk or moderately increases AD risk [40-42]. Although the effects of smoking on memory and AD risk are inconclusive, the effects of nicotine on cognitive ability are still of interest. In addition to modulating cholinergic activity, nicotine has shown other activities which may be relevant in some neurodegenerative diseases featuring memory loss. Nicotine inhibits P-amyloid formation in vitro [43,44], inhibits the neurotoxic effects of glutamate  and also enhances the effects of nerve growth factor (NGF) .
A number of other alkaloids are reported to be nicotinic agonists and could therefore be investigated, or their structures modified, to develop new therapeutic compounds. Alkaloids including lobeline (5) from Lobelia inflata L. (Campanu-laceae) and cytisine (6), found in a number of plants including species of Sophora
(Leguminosae), have binding affinity for nicotinic receptors [46-49], but these compounds do not appear to have been developed for any pharmaceutical purposes, perhaps due to toxicity.
Inhibition of ACh (1) hydrolysis by AChE, through the use of AChE inhibitors, has been a more successful approach than attempts to use compounds which directly stimulate cholinergic receptors to modulate cholinergic function, as AChE inhibitors prolong the half-life of ACh, and therefore the availability of ACh released into the neuronal synaptic cleft.
Over the last decade, some AChE inhibitors have been licensed for clinical use for the symptomatic relief of mild to moderately severe AD. However, these drugs only alleviate some of the cognitive symptoms of the disease, rather than treat the disease, and may not be effective in some patients. The synthetic drug tacrine (7) (Cognex) was the first AChE inhibitor to be licensed, but its use was limited by adverse effects, including hepatotoxicity [50, 51]. The current AChE inhibitors licensed for use in AD include donepezil (8) (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) , with the latter two drugs based on naturally derived compounds. In addition to modulating cholinergic function, some AChE inhibitors are reported to interfere with ^-amyloid metabolism and thus could reduce senile plaque formation, one of the pathological occurrences in AD .
Some reports have indicated that the use of anti-inflammatory compounds may modify the progression of AD, since inflammatory processes have been linked with AD pathology [54-57]. Some studies have indicated that non-steroidal antiinflammatory drugs (NSAIDs), which inhibit cyclo-oxygenase (COX) activity, may reduce the risk of developing AD, and patients with rheumatoid arthritis, who often use NSAIDs, are suggested to have a lower incidence of AD [58-62]. In addition to inhibition of COX, it has also been suggested that NSAIDs may act via other mechanisms such as anti-amyloidogenic effects . In view of the adverse effects commonly associated with COX inhibitors currently in clinical use , new anti-inflammatory compounds may be developed, including those which are naturally derived, which may have potential in modifying the progression of cognitive disorders such as AD with fewer adverse effects.
There are numerous examples of plant extracts and their constituents which display anti-inflammatory effects [64-68]. Consequently, there is some potential for novel anti-inflammatory agents to be identified from plant sources, although plants as a source of new anti-inflammatory drugs have not been extensively exploited to achieve this aim. Various flavonoids have been associated with anti-inflammatory activity [65, 66, 69] and may have potential for use in some CNS disorders in which inflammatory processes are known to occur. Some structural features of flavonoid molecules required for COX inhibition are considered to be the presence of a pyro-catechol group in at least one of the flavonoid rings; however, flavones lacking these substituents can also inhibit COX [68, 69]. Other plant-derived compounds with potential for use in inflammatory disorders include ferulic acid, which is an antiox-idant and anti-inflammatory compound. Ferulic acid is of interest since it ameliorated the reduction in ACh (1) levels in the cortex and the inflammatory responses in the hippocampus induced by P-amyloid in mice and, significantly, it also improved cognitive function .
Antioxidants have been suggested to reduce the risk of developing dementia, although evidence to support this hypothesis is under review . Free-radical reactions, which are reported to initiate cell injury, have been implicated in the pathology of various diseases including ageing processes, atherosclerosis, ischemic heart disease and neurodegenerative diseases which involve cognitive impairment [72-74]. Antioxidants have therefore been considered as a means to modify and minimise neuronal degeneration in cognitive disorders.
A wide variety of plants have been associated with antioxidant effects [75-77]. It is therefore not surprising that many different and structurally diverse phyto-chemicals have also shown antioxidant activity, including some cinnamic acids, coumarins, diterpenoids, flavonoids, monoterpenoids, phenylpropanoids and tannins [78-84]. The antioxidant properties of Camellia sinensis Kuntze (Theaceae), commonly known as green tea, are well documented, and some studies suggest that C. sinensis extracts and some of the catechin components have protective mechanisms in neurodegenerative disorders . For example, (-)-epigallocatechin gallate
(9) had protective effects against ^-amyloid-induced neurotoxicity in vitro, an effect associated with its scavenging reactive oxygen species . However, the ability of the catechins to cross the blood-brain barrier may be restricted due to their polarity, thus limiting any therapeutic effect in practice.
Although many plants and their compounds have shown antioxidant effects in vitro, relatively few have been explored for their therapeutic and clinical relevance, particularly in relation to cognitive disorders. One plant which has shown favourable effects in the CNS is Thymus vulgaris L. (Lamiaceae). A study investigating T. vulgaris essential oil showed that it maintained higher polyunsaturated fatty acid (PUFA) levels in various tissues, including the brain in rats, indicating protective antioxidant effects . Other examples of plants which show antioxidant activity, particularly with reference to CNS pathologies, are described later in this chapter.
For a number of years, conclusions from epidemiological evidence indicated that estrogen-replacement therapy (ERT) had a preventative role against AD development, and estrogen treatment in women with AD enhanced cognitive function [88-91]. The mechanisms by which estrogens may protect against AD are unclear but may be mediated via interaction with estrogen receptors in the CNS, or perhaps by effects on neurotransmitter systems, modulation of NGF, enhancement of cerebral blood flow or antioxidant effects [92-94] or other unknown mechanisms. However, evidence from some more recent studies [95, 96] does not support an association between high estrogen levels and a reduced incidence of AD. Nevertheless, the estrogenic activities of some plant extracts have been explored as one possible explanation for their reputed memory-enhancing effects [97, 98].
Soya beans, the seeds of Glycine max Merr. (Leguminosae), form an important part of the traditional diet in China and other parts of the Far East and are frequently a staple of the diet of vegetarians and vegans. Soya contains isoflavones including genistein (10) and daidzein (11), which have been characterised as phytoestrogens.
9 Epigallocatechin 3-O-gallate
9 Epigallocatechin 3-O-gallate
Some studies indicate that phytoestrogens may alter anxiety, learning and memory in vivo . Phytoestrogens, particularly the soya isoflavones, are reported to improve cognitive function, not only in some animal studies but also in some clinical studies, and have been suggested to offer protection against AD development [100-102]. One study in student volunteers suggested that a high soya diet (100 mg total isoflavones/d for 10 weeks) may improve short- and long-term memory in both females and males . Another study showed that consumption of soya isoflavones by postmenopausal women for a period of 12 weeks improved cognitive function . In a double-blind, randomised, placebo-controlled trial, some cognitive benefits, particularly verbal memory, occurred in postmenopausal women taking isoflavone supplements for 6 months .
The mode of action of phytoestrogens to explain favourable effects on cognition is unclear, and they may act similarly to ERT and via interaction with the estrogen receptor or by other mechanisms, perhaps independently of the estrogen receptor. For example, genistein showed a neuroprotective effect against (i-amyloid-induced neurotoxicity in vitro , and it ameliorated ^-amyloid peptide-induced hippocampal neuronal apoptosis in vitro, which could be associated with an antioxidant effect . It has been proposed that although phytoestrogens may exert some neuroprotective effects analogous to that of antioxidants, they are not functionally equivalent to the endogenously active estrogens .
Many other plants have been considered to display estrogenic effects in some studies, but their physiological significance and any potential clinical relevance in improving cognition require further investigation. Pueraria lobata (Willd.) Ohwi (Leguminosae), a plant used in traditional Chinese medicine (TCM), and some of its component isoflavones (e.g. puerarin (12)) have shown estrogenic activity in vitro . Puerarin also attenuates the deficits of inhibitory avoidance performance in rats, which was associated with an increase in cholinergic activity via nico-tinic, but not muscarinic, receptors, in addition to activation of N-methyl-D- aspartate (NMDA) receptors, and a decrease in serotonergic neuronal activity . Another study in which postmenopausal women were treated with P. lobata (equivalent to 100 mg isoflavones) for 3 months suggested it could promote some favourable effects on cognitive function . It is apparent that some phytoestrogens do show potential for use in some cognitive-related disorders, but more extensive and longer-term studies are needed.
Glutamate may induce neuronal degeneration by overstimulation of NMDA receptors. NMDA receptor modulators may have potential use in some CNS disorders including schizophrenia, stroke, epilepsy, Parkinson's disease, Huntington's disease and AD . Memantine (13) (Ebixa), an uncompetitive NMDA receptor antagonist, is reported to be neuroprotective , is a licensed drug for the treatment of AD symptoms and has been shown to be therapeutically effective in AD patients [112, 113].
15.3 Plants as a Source of Useful Therapeutic Agents in Cognitive Diseases
Numerous plants are reputed in traditional practices of medicine to alleviate the cognitive decline that can be associated with general ageing, but they may also be relevant in the treatment of specific cognitive disorders such as AD and other dementias. Thus, plants reputed to have 'anti-ageing' or 'memory-enhancing' effects could also be considered for their potential efficacy in disorders now recognised to be associated with cognitive dysfunction, including those conditions in which dementia occurs.
A mixture of plants is commonly prescribed in some practices of traditional medicine including Ayurveda and TCM. The plant constituents may not only act synergistically with other constituents from the same plant, but they may also enhance the activity of compounds from other plants in a particular remedy or herbal formula. For example, the interaction of a compound at a target receptor may affect the activity of another compound at that receptor, possibly due to allosteric effects, which can occur at some types of receptor . An ethnopharmacological approach can assist with the search for plants and, eventually, potential new drugs that could be relevant for the treatment of cognitive disorders, including AD.
There are numerous examples of plants used in various traditional practices of medicine which have a reputation for influencing cognitive functions. However, relatively few of these plants have been investigated to establish any scientific basis for their reputed effects. The plants described below are mainly those which have
13 Memantine stimulated an interest in establishing a pharmacological basis for the reputed effects. It should also be considered that there are many other traditional medicines which have yet to be investigated for a scientific basis to explain their traditional uses and many that have shown interesting biological activity in some studies but which have not been investigated extensively. Although some of these remedies have been promoted as 'alternative' or 'complementary' therapies, in many instances, there is a lack of substantial evidence for their efficacy and safety or their potential interactions with other medicines. Some of these remedies may contain compounds which are more active when combined in a mixture than when isolated and used alone. Thus, the use of a plant extract may be preferred to single isolated constituents. In addition, in a mixture such as an extract, there may be a variety of compounds with polyvalency, i.e. the different compounds present act in a number of different but relevant ways, and at different molecular targets to produce the overall pharmacological effects for treating a particular condition.
Ayurvedic medicine is the oldest medical system in the world with written records in Sanskrit dating back at least 5000 years. It originates from the Indian subcontinent and has also influenced the traditional medical system in Thailand. The practice of Ayurvedic medicine is now widely used throughout the world as a complementary medicine.
Arecoline (14) is the major alkaloid of those present in betel or areca nuts, the fruit of the palm tree Areca catechu L. (Arecaceae), which is extensively chewed to induce salivation and euphoria throughout the Indian subcontinent and other parts of southeast Asia. It is estimated that 500 million people regularly chew betel nut (often referred to as 'pan' or 'paan' in India) in a form which is usually shredded, mixed with lime and wrapped in a leaf from the Piper betel Blanco (Piperaceae) plant, although chewing of betel nuts has been positively correlated with an incidence of oral cancer . As a direct result of the cholinergic activity induced by this plant, excessive salivation occurs, which is associated with a muscarinic effect, and CNS stimulatory and euphoric effects develop, which is considered to be associated with a nicotinic receptor stimulant effect .
Arecoline has been reported as an Mi/M3 partial agonist  and was shown to bind to M2 muscarinic receptors . Arecoline has been considered as a treatment for cognitive impairment since it showed improvement in scopolamine-induced cognitive impairment and passive avoidance performance in vivo, indicating a choliner-gic action [119, 120]. When arecoline was administered to AD patients, it enhanced verbal memory  and moderately improved cognitive function and recognition skills [122, 123].
Derivatives of arecoline have been synthesised in order to improve selectivity for cortical muscarinic receptors. Examples of arecoline derivatives include xanomeline (2), reported to be functionally selective for the Mi receptor , which delayed cognitive decline and reduced hallucinations and delusions when given to AD patients . Other derivatives of arecoline are Lu 25-109-T and talsaclidine, which are also M1 functionally selective receptor agonists. Although Lu 25-109-T showed encouraging results in vitro , it failed to improve cognition when tested clinically in patients with mild to moderate AD . Talsaclidine has been shown to increase cholinomimetic central activation in animals and humans without some of the side-effects observed with AChE inhibitor therapy, but higher doses are linked with adverse effects including salivation and sweating, and, disappointingly, cognitive function was not significantly improved with this compound [22, 126]. Other tests on rhesus monkeys did show some improvement in memory-related tasks, but at doses which produced unacceptable adverse effects .
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