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.

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