X-Message-Number: 12907 Date: Mon, 06 Dec 1999 21:07:39 -0500 From: Jan Coetzee <> Subject: Lethal Weapons: Neurons "Ideally, these could then be given to people at risk of a stroke, before it even occurs, so that if and when it does, the damage and suffering is minimized" -- Lethal Weapons - Neurons that Pump Out Glutamate by Julie Clayton A stroke occurs when a blood clot or hemorrhage causes a loss of blood supply to parts of the brain. The greatest damage, however, appears later, due to a chain of events that lead to a more widespread loss of neurons. Meticulous studies by Dr David Attwell and his colleagues at University College London, UK, now reveal that the neurons themselves become their own worst enemy. A pump in their cell membrane that normally ensures a safe external milieu, is tricked into going into reverse, pumping out of the cell the neurotransmitter glutamate, which it should instead be mopping up. The consequences are lethal to the neurons, says Attwell, presenting his findings at the Society for Neuroscience in Miami Beach October 26, 1999. The brain is comprised of millions of nerve cells and glial cells, which together form the intricate communication network that is vital to brain function. Both types of cells have a number of surface channels and receptors in common, and recent studies show that glial cells, particularly astrocytes, have an important role in regulating neuronal activity. Part of this regulation involves controlling the levels of substances in the extracellular space around the synaptic junctions between neurons. Once a neuron has released glutamine across the synapse to stimulate the next to send an action potential, special pumps in the membranes of both astrocytes and neurons switch on to remove glutamate again so that the stimulation ceases. When a stroke occurs, it is known that the neurotransmitter glutamine instead builds up in the extracellular space. For some reason, the glutamate removal mechanism has failed. This causes over stimuation to the neurons, which then accumulate dangerous levels of intracellular calcium, and eventually cell death. The question that Attwell set out to answer was which cells are failing to mop up the glutamate, and why? The answer could lead to new approaches to preventing the damage caused by stroke. Attwell had already established that the glutamate transporter pump of neurons depends for its power on the flow of sodium into the cell, which occurs as part of the cycle of generating an action potential. Another pump then returns sodium back out again. By performing cell culture experiments to mimic the situation of a stroke, Attwell has now found that while astrocytes continue in their attempt to remove the excess glutamate from the extracellular space, the glutamate transporter in neurons is doing the reverse. It appears that the lack of oxygen and glucose supply leads to a failure in the sodium pump, with the result that the external level of acidity rises, and sodium falls, as it begins to accumulate internally. The glutamate pump is then unable to remove external glutamate. Sodium then begins to flow out of the cell again, in an attempt to equalize its concentrations on either side of the membrane, and glutamate goes with it, thereby raising the extracellular concentration to dangerous levels. Having so elegantly elucidated the mechanism by which neuronal cell death follows stroke, Attwell suggests that the implications for the design of new treatment is to create substances that block the triggering of neuronal receptors by the excess glutamate. While some NMDA blockers already exist, these have side effects when given to patients, and it would be better to have versions that only act in conditions of raised acidity, as found immediately after a stroke. Ideally, these could then be given to people at risk of a stroke, before it even occurs, so that if and when it does, the damage and suffering is minimized. This could include newborn babies who may have had a difficult birth and whose brains have been deprived of oxygen, he says. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=12907