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J Neurophysiol (November 1, 2002). 10.1152/jn.00321.2002
Submitted on 30 April 2002
Accepted on 29 July 2002
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada
Anderson, Trent R. and
R.
David Andrew.
Spreading Depression: Imaging and Blockade in the Rat Neocortical
Brain Slice. J. Neurophysiol. 88: 2713-2725, 2002. Spreading depression (SD) is a profound but transient
depolarization of neurons and glia that migrates across the cortical and subcortical gray at 2-5 mm/min. Under normoxic conditions, SD
occurs during migraine aura where it precedes migraine pain but does
not damage tissue. During stroke and head trauma, however, SD can arise
repeatedly near the site of injury and may promote neuronal damage. We
developed a superfused brain slice preparation that can repeatedly
support robust SD during imaging and electrophysiological recording to
test drugs that may block SD. Submerged rat neocortical slices were
briefly exposed to artificial cerebrospinal fluid (ACSF) with KCl
elevated to 26 mM. SD was evoked within 2 min, recorded in layers
II/III both as a negative DC shift and as a propagating front of
elevated light transmittance (LT) representing transient cell swelling
in all cortical layers. An SD episode was initiated focally and could
be repeatedly evoked and imaged with no damage to slices. As reported
in vivo, pretreatment with one of several
N-methyl-D-aspartate (NMDA) receptor antagonists blocked SD, but a non-NMDA glutamate receptor antagonist (CNQX) had no
effect. NMDA receptor (NMDAR) activation does not initiate SD nor are
NMDAR antagonists tolerated therapeutically so we searched for more
efficacious drugs to block SD generation. Pretreatment with the
sigma-one receptor (
1R) agonists dextromethorphan
(10-100 µM), carbetapentane (100 µM), or 4-IBP (30 µM) blocked
SD, even when KCl exposure was extended beyond 5 min. The block was
independent of NMDA receptor antagonism. Two 1R
antagonists [(+)-3PPP and BD-1063] removed this block but had no
effect upon SD alone. Remarkably, the 1R agonists also
substantially reduced general cell swelling evoked by bath application
of 26 mM KCl. More potent 1R ligands that are
therapeutically tolerated could prove useful in reducing SD associated
with migraine and be of potential use in stroke or head trauma.
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