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Volume 16, Number 16,
Issue of August 15, 1996
pp. 5004-5013
Copyright ©1996 Society for Neuroscience
Vicious Cycle Involving Na+ Channels, Glutamate
Release, and NMDA Receptors Mediates Delayed Neurodegeneration through
Nitric Oxide Formation
Received March 5, 1996; revised May 23, 1996; accepted June 3, 1996.
Paul J. L. M. Strijbos,
Michael J. Leach, and
John Garthwaite
Neuroscience Research, Wellcome Research Laboratories, Beckenham,
Kent BR3 3BS, United Kingdom
The mechanisms by which neurons die after cerebral ischemia and
related conditions in vivo are unclear, but they are thought
to involve voltage-dependent Na+ channels,
glutamate receptors, and nitric oxide (NO) formation because selective
inhibition of each provides neuroprotection. It is not known precisely
what their roles are, nor whether they interact within a single cascade
or in parallel pathways. These questions were investigated using an
in vitro primary cell culture model in which striatal
neurons undergo a gradual and delayed neurodegeneration after a brief
(5 min) challenge with the glutamate receptor agonist NMDA.
Unexpectedly, NO was generated continuously by the cultures for up to
16 hr after the NMDA exposure. Neuronal death followed the same general
time course except that its start was delayed by ~4 hr. Application
of the NO synthase inhibitor nitroarginine after, but not during, the
NMDA exposure inhibited NO formation and protected against delayed
neuronal death. Blockade of NMDA receptors or of voltage-sensitive
Na+ channels [with tetrodotoxin (TTX)] during
the postexposure period also inhibited both NO formation and cell
death. The NMDA exposure resulted in a selective accumulation of
glutamate in the culture medium during the period preceding cell death.
This glutamate release could be inhibited by NMDA antagonism or by TTX,
but not by nitroarginine. These data suggest that
Na+ channels, glutamate receptors, and NO operate
interdependently and sequentially to cause neurodegeneration. At the
core of the mechanism is a vicious cycle in which NMDA receptor
stimulation causes activation of TTX-sensitive
Na+ channels, leading to glutamate release and
further NMDA receptor stimulation. The output of the cycle is an
enduring production of NO from neuronal sources, and this is
responsible for delayed neuronal death. The same neurons, however,
could be induced to undergo more rapid NMDA receptor-dependent death
that required neither TTX-sensitive Na+ channels
nor NO.
Key words:
striatum;
glutamate;
excitotoxicity;
NMDA receptors;
sodium channels;
nitric oxide
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