Science: Tastes so good it will leave you twitching: Glutamate helps to flavour Chinese food, but it also has a role in strokes and Alzheimer's disease, writes Ruth McKernan
Monday 10 August 1992
People stepped over me with the sympathy usually reserved for English football fans abroad. It was my first trip to the Orient, my first delicious thick and spicy soup, and my first encounter with 'Chinese restaurant syndrome'.
The syndrome is caused by glutamate, which is added to oriental food as the flavour enhancer monosodium glutamate (MSG). But Chinese restaurant syndrome is the least serious of the conditions associated with this molecule: glutamate is responsible for the brain damage that can result from strokes, which rank as the third-largest cause of death in Western Europe and North America, after cancer and heart disease.
Glutamate is also a primary factor in the memory loss suffered in Alzheimer's disease, and the hallucinations experienced by those who take the illicit drug PCP.
Glutamate is one of the chemical messengers present in the brain responsible for transmitting information from one cell to another. It works by binding to 'receptors' - specific sites on the surface of the brain cell that recognise the chemical - rather as a key fits into a lock. For years, biochemists have known that glutamate acts as a pass key - it can open four types of lock.
Last month, however, they discovered that there is a much richer variety of receptors than they had thought. By analysing how these receptors differ from one another, they hope to develop new drugs to prevent the sort of paralysing brain damage that results from strokes. It may even be possible to slow the loss of memory characteristic in those suffering from Alzheimer's disease.
German researchers have isolated the genes responsible for the receptors and, by inserting the genes into cells cultured in the laboratory, can now study each receptor individually.
Glutamate is present in small amounts in every cell in the body and brain cells make their own glutamate. Normally, it does not get from the blood into the brain unless present in excessive amounts; it was only because the meal I ate in Tokyo contained so much MSG that concentrations in my blood were high enough for some of it to pass into my brain, causing me to be ill. Even then it only reaches one specialised region, the hypothalamus, a cherry- sized structure at the front of the brain responsible for many functions, including muscle control and blood pressure. The glutamate I ingested, albeit deliciously disguised, may have caused my symptoms by overstimulating cells in the hypothalamus.
Overstimulation is also the key to the brain damage suffered when someone has a stroke. Glutamate is normally released from brain cells only in small, controlled amounts. A stroke, or a severe head injury, interferes with the blood supply to the brain, reducing the supply of essential nutrients, oxygen and glucose, to the cells. Without a continuous supply of energy, the cell cannot hold in its glutamate and it pours out, overstimulating the adjacent cells and triggering a series of internal chemical reactions. Ultimately, the cells are made to work so hard that they burn out - they are literally excited to death.
Jim McCulloch, whose team at Glasgow University comprises world leaders in the search for possible treatments for stroke, says: 'Dead brain cells can never be replaced and we have no drugs at present that can protect them.' But Professor McCulloch believes there may be ways of blocking the action of glutamate and so preventing brain damage.
Although there are four types of glutamate receptor, one of them - the NMDA receptor - is the most important in cell death. Pharmaceutical companies are developing drugs that will block this one type of receptor but still allow glutamate to act on the others. 'By using receptor-selective drugs, we can take out the lethal system but leave others unaffected,' says Professor McCulloch.
Drugs that block the NMDA receptor are undergoing clinical trials in the US and Britain. 'They undoubtedly save brain cells, even if given a few hours after a stroke. But you would take these drugs only for a few days in an emergency,' warns Professor McCulloch, because the side-effects can be severe. NMDA receptors normally control memory, thought processing and movement. Patients who take drugs to block these receptors could experience side-effects ranging from drowsiness to hallucinations.
The side-effects came as little surprise to researchers. About five years ago American scientists realised that PCP, also known as 'angel dust', which has been much abused in the US for its mind-bending properties, blocks the NMDA receptors.
'We now know enough about how glutamate can cause brain damage to see where drugs will work,' says Professor McCulloch. 'This is one of the areas where Britain has been at the forefront of research internationally.'
Drugs that block glutamate receptors impair memory. If it were possible to do the opposite - make glutamate receptors work a bit better - this might offer a mechanism for improving memory and a treatment for some of the symptoms of Alzheimer's disease.
In Alzheimer's disease, 'many cells that use glutamate degenerate', says David Bowen, Reader in Neurochemistry at the Institute of Neurology in London.
This causes two problems. First, as the cells die, the outflow of glutamate can kill their neighbours. Second, once the original cells have disappeared, the opposite problem ensues - there is too little glutamate. At a biochemical level, memory depends on cells being regularly stimulated by glutamate, but surviving neighbouring cells get too little stimulation and normal processes of memory are lost.
'It may be that the loss of some cells is particularly important - either because of their location, or they may have a type of receptor which makes them more vulnerable than most,' suggests Dr Bowen, who has been studying the involvement of glutamate in Alzheimer's disease for 10 years.
Last month, a team of researchers in Heidelberg, led by Peter Seeberg, applied the latest techniques of modern genetics to discover that there are several different types of NMDA receptors. Dr Ralf Schoepfer, a senior member of the German team, says: 'So far there are four forms, but we are convinced that there are more, we do not yet know how many.' The beauty of the Germans' procedure is that it opens the way to insert individual receptors into cells cultured in the laboratory and then use these designer receptors for testing potentially active drugs.
By sorting out the different types of receptors and studying how different compounds interact with them, it should be possible to develop drugs that are precise in their mode of action and which have fewer unwanted side-effects.
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