The benefits to memory of biological activities in tea

The benefits to memory of biological activities in tea

One of the most disabling features of the ageing process and in certain neurodegenerative diseases is cognitive dysfunction, particularly loss of memory (dementia). Dementia is a chronic, progressive neurodegenerative disorder with characteristic deterioration of intellectual capacity in various domains: learning and memory, language abilities, reading and writing, praxis and interaction with the environment¹.

Over time, sufferers become unable to perform the activities of daily living (ADL), and personality changes occur, leading to behavioural disturbances. As the disease progresses patients become increasingly dependent on the care of others, and this has a major practical and emotional impact on the lives of the carers and other members of the family. There are a number of dementia types: Lewy body dementia, dementias associated with cerebrovascular disease, Parkinson’s disease, Picks disease and Alzheimer’s disease (AD). Alzheimer’s Disease is a major cause of morbidity and mortality and is the most common type of dementia, accounting for 50-60 per cent of dementia cases in persons over 65 years of age². There are over 15 million people suffering from AD worldwide.

Dementia associated with AD

The aetiology of AD is not yet fully understood. There is however a solid scientific understanding of the pathological features in the central nervous system (CNS) which are associated with cognitive dysfunction. The typical underlying pathology³ is characterised by a number of features: cortical atrophy in the frontal and temporal lobes, oxidative and inflammatory processes, loss of neurons and synapses – bringing about neurotransmitter disturbances, formation of neurofibrillary tangles (consisting of the accumulation of abnormal components of the neuronal cytoskeleton) and senile plaques (which have a core of beta-amyloid peptide, with dystrophic neurites and glial elements at the periphery).

Cerebral activity and memory

It is well established that the cholinergic system is adversely affected in the brains of patients with AD⁴. Cholinergic functions are dependent upon maintaining the balance between the production, release and breakdown of the neurotransmitter acetylcholine (ACh). An imbalance in any of these processes will manifest in cognitive dysfunctions such as memory loss. It is also well established that there is extensive loss of cholinergic neurons in AD, particularly the areas of the brain associated with learning and memory. These areas are neocortex, amygdala and hippocampus¹. Levels of choline acetyltransferase (ChAT), the enzyme responsible for the synthesis of ACh, also decrease in AD^{5, 6}, which means that levels of ACh are also reduced. Cognitive function has been shown to be dependent on cholinergic innervation of the cortex^{1, 6, 7}. This is demonstrated by the correlation between the decrease in ChAT, increase in senile plaques and cognitive impairment. This has led to the development of the cholinergic hypothesis of AD, which suggests that the loss of cholinergic transmission contributes to the causation of the symptoms of AD. This is probably not a primary trigger of the disease but rather a secondary cause brought on by cell damage.

ACh also acts on nicotinic and muscarinic receptors⁷ which are important for information processing. The number of nicotinic receptors decreases in AD, but nicotinic agonists can up-regulate the receptor. By increasing levels of ACh the nicotinic receptors may be indirectly up-regulated. The receptors themselves are not directly affected by the AChE inhibitors^{7, 8}. It should be pointed out that muscarinic receptors are relatively well preserved¹; therefore, the ACh conserved by the cholinesterase inhibitor can still be effective.

Butyrylcholinesterase (BuChE) is another enzyme associated with glial cells and neurons⁹. It is also present in neurofibrillary tangles and senile plaques. There is no evidence to date to show that it is involved in the processes underlying cognition. However, it may be involved in the regulation of other proteins. BuChE has been shown to increase by between 40-90 per cent in patients with AD, particularly in the cortex and hippocampus, areas of the brain associated with cognitive function¹⁰. It is now suggested that BuChE may play a role in the progression of AD by its ability inter alia to hydrolyze ACh¹¹.

Beta-secretase is another enzyme associated with the pathology of AD. This enzyme is involved in the production of beta-amyloid peptides (ABeta) via cleavage of amyloid precursor protein (APP). The deposition and aggregation of ABeta are said to be key events in the onset, progression and pathogenesis of AD¹².

Free radicals, composed of reactive oxygen species (ROS) and reactive nitrogen species (RNS) such as superoxide, hydroxyl and nitric oxide, are known to initiate cell injury and are implicated in the ageing process and in the pathology of neural damage after global ischaemia, atherosclerosis and neurodegenerative diseases including AD^{13. 14, 15}.

Current pharmacology

The current medications available for the treatment of the AD seek to manipulate the cholinergic system in order to correct cognitive dysfunction. Drugs have been developed which inhibit acetylcholinesterase (AChE), which is one of the enzymes responsible for breaking down ACh. By inhibiting AChE these drugs increase the levels of ACh available at the synapse, and thus enhance neurotransmission. AChE is also known to accelerate the assembly of beta-amyloid peptides into fibrils¹⁶. AChE inhibitors may therefore have a role in decreasing the formation of plaques, and thereby slowing down the progress of the disease.

Drugs which are thought to be useful in the treatment of symptoms of AD include: tacrine (Cognex), donepezil (Aricept), physostigmine, eptastigmine, galanthamine and metrifonate. Whilst bringing some benefits to AD patients these drugs can also have some detrimental side effects. Tacrine for example can bring about hepatotoxicity. Donepezil is currently prescribed for mild to moderate AD, and has been shown to be more effective than placebos in double-blind clinical trials. It lacks any adverse effects and is easy to use, however it does not slow the progress of the disease. Although it is able to inhibit AChE, it is less effective in the cortex, one of the areas of the brain associated with AD¹⁷. Physostigmine inhibits AChE uniformly throughout the grey matter¹⁸. It has been the subject of a number of clinical trials¹⁹, but its efficacy is uncertain as it has a short biological action and a low bioavailability. It is not selective for AChE and it has a narrow therapeutic window.

Studies on the physostigmine derivative, eptastigmine, have proved to be more promising: it achieves a high inhibition of AChE within a few hours, and then the reaction slows down so that 100 per cent inhibition is not achieved (and indeed is not desirable). In clinical trials, it has been shown to bring about cognitive improvement, especially in the more deteriorated patients¹. However, neutropaenia may be a side effect. Other physostigmine derivatives are being developed and tested¹⁸. Galanthamine (isolated from snowdrops) has been shown to bring about some beneficial impact in clinical trials¹. Metrifonate has also been shown to be of benefit but can have some cholinergic side effects¹. The actual effectiveness of some of the current drug treatments is difficult to evaluate because in clinical trials these drugs were only compared with placebos and most subjects were patients suffering from mild to moderate dementia rather than those suffering from more severe symptoms of the disease¹.

Drugs in development for treatment of AD

There is a number of drugs currently being developed and clinically tested which purport to effective in a number of areas beneficial to the treatment of AD, for example: butyrylcholinesterase inhibition, preventing amyloid formation (e.g. beta-secretase inhibitors), modulating nicotinic or muscarinic receptors, antagonising glutamate receptors, being anti-inflammatory and hypocholestrolemic. Because of the complexity and diversity of the pathological causes of AD, the treatments that will be developed in the future are most likely to be poly-pharmacological in approach.

In AD management, an ideal treatment should seek to maintain a balance in cognitive function, halt or slow down the progress of the disease. This will have the effect of prolonging the patient’s ability to perform the activities of daily living and will minimise behavioural disturbances. This will have the overall effect of prolonging and improving quality of life of both patients and their carers and potentially reducing the cost of care.

A cup of tea – a potential treatment for AD

Tea is the most commonly drunk beverage after water. There are three types – black, oolong and green tea, all three being obtained from the same plant, Camellia sinensis, and differing only in the way they have been manufactured. Black tea is oxidised during the manufacturing process whereas green tea is not, while oolong tea is partially oxidised. The quality of tea, like that of wine, is determined by many factors such as the variety of the tea shrub, where it is grown, the climate, the altitude, the soil type, the time of picking and the manufacturing process²⁰.

The manufacturing process does affect the chemical content and flavour of the tea²¹. Green tea contains more catechins (simple flavonoids) whereas in black tea these undergo oxidation into more complex forms called theaflavins and thearubigins. Green tea is consumed mainly in the far Eastern countries like Japan, and China, whereas black tea is more popular in the West. For many centuries, Chinese herbalism has attributed health benefits to Camellia sinensis.

It is already well established that both black and green teas possess many pharmacologically protective properties. These include antioxidative²² anticarcinogenic²³, hypocholesterolaemic²⁴ and neuroprotective²⁵ properties. All of these attributes would be of benefit in the treatment AD.

Research carried out at the Medicinal Plant Research Centre at the University of Newcastle upon Tyne has established that both black and green tea interact with key biochemical markers of AD²⁶. This discovery identifies tea as an inhibitor, in vitro, of the activities of human AChE , BuChE and beta-secretase . This has the potential effect of increasing the levels of ACh, enhancing neurotransmission and thereby improving memory and other cognitive functions.

In a series of experiments carried out to investigate the properties of Doewe Egberts coffee, Chinese gunpowder green tea and traditional English black tea – PG tips, the researchers found that coffee has no effect on key enzymes associated with AD. However, both black and green have the effect of inhibiting the activities of both AChE and BuChE in a concentration-dependent manner, with green tea being far more potent in its effectiveness. The researchers also found that green tea obstructs the activity of beta-secretase, the enzyme that plays a role in the production of the amyloid protein deposits found in brains of some patients with AD.

Research, soon to be published, on human subjects over the age of 80 years corroborates these in vitro findings in terms of effects of drinking green tea on cognitive function. We have evidence that lifestyle habits such as alcohol consumption may negate the cognitive benefits of tea.

Anti-oxidant and anti-inflammatory activities

Tea is well known for its antioxidant properties, mainly due to polyphenols constituents. These have been shown to be efficient chemoprotectors against ROS and RNS. Provided they are bio-available, the use of tea-derived anti-oxidants may therefore be used to slow the progression of AD by minimising neural damage and death caused by these free radical species^{27, 28}.

Inflammation is another process that has been implicated in AD. There are reports that the use of non steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of developing AD^{29, 30}. However, the anticholinesterase activity of tea may also have a role in combating inflammation through the “cholinergic anti-inflammatory pathway”. It is well known that macrophages (immune cells) express ACh receptors. Inhibition of AChE and BuChE results in increased levels of ACh. ACh is also a functional ligand for the alpha7 nicotinic ACh receptor subunit (nAChR) on macrophages³¹. Upon the binding of ACh to this subunit, suppression of pro-inflammatory tumor necrosis factor (TNF), acytokine, known to mediate inflammatory responses, occurs. Glial-derived TNF interacts with neurons as part of an injury or inflammatory process³², causing apoptosis via the cell death receptor pathway³³ in the early stages of neural degeneration in AD³⁴. Evidence in vivo also shows that such interactions may induce axonal damage to cholinergic nerve terminals and nerve fibres, possibly leading to subsequent cell death of cholinergic neurons in the basal nucleus of Meynert³⁵. Thus, glial and neural inhibition of AChE and BuChE with dual anti-cholinesterase activity may have an indirect neuroprotective role through controlling the over-expression of TNF.

A simple cup of tea, therefore, has the potential to provide a phytochemical and poly-pharmacological approach to enhancing memory and treating symptoms associated with AD at significantly less cost and with few side effects than current pharmacological treatments. Further research is required and we intend to:

Test a range of tea products for ability to interact with key biochemical markers associated with memory/ AD.

Assess bioavailability of the biologically active constituents.

Determine synergy/ antagonism amongst constituents with a view to concocting a standardized medicinal tea with memory enhancing activity.

Formulate poly-pharmacologically active bespoke teas as remedies for different types and degrees of dementia.

Conduct clinical trials of standardised teas/ tea extracts.

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Dr Ed Okello is the executive director of the Medicinal Plant Research Centre at the University of Newcastle Upon Tyne, and lead researcher on tea and its potential beneficial effects