Brain Research 887 2000 301–308 www.elsevier.com locate bres
Research report
Effect of a neuronal sodium channel blocker on magnetic resonance derived indices of brain water content during global cerebral ischemia
a,b b
c b ,
Herbert Koinig , John P. Williams , Michael J. Quast , Mark H. Zornow
a
Department of Anesthesiology and General Intensive Care , University of Vienna, Vienna, Austria
b
Department of Anesthesiology , The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0591, USA
c
Marie Hall Magnet Laboratory , Marine Biomedical Institute and Department of Anatomy and Neuroscience,
The University of Texas Medical Branch , 301 University Boulevard, Galveston, TX 77555-0591, USA
Accepted 19 September 2000
Abstract
Diffusion-weighted magnetic resonance imaging DWI with calculation of the apparent diffusion coefficient ADC of water is a widely used noninvasive method to measure movement of water from the extracellular to the intracellular compartment during cerebral
1
ischemia. Lamotrigine, a neuronal Na channel blocker, has been shown to attenuate the increase in extracellular concentrations of
excitatory amino acids EAA during ischemia and to improve neurological and histological outcome. Because of its proven ability to reduce EAA levels during ischemia, lamotrigine should also minimize excitotoxic-induced increases in intracellular water content and
therefore attenuate changes in the ADC. In this study, we sought to determine the effect of lamotrigine on intra- and extracellular water shifts during transient global cerebral ischemia. Fifteen New Zealand white rabbits were anesthetized and randomized to one of three
groups: a control group, a lamotrigine-treated group, or a sham group. After being positioned in the bore of the magnet, a 12-min 50-s period of global cerebral ischemia was induced by inflating a neck tourniquet. During ischemia and early reperfusion there was a similar
and significant decrease of the ADC in both the lamotrigine and control group. The ADC in the sham ischemia group remained at baseline throughout the experiment. Lamotrigine-mediated blockade of voltage-gated sodium channels did not prevent the intracellular movement
of water during 12 min 50 s of global ischemia, as measured by the ADC, suggesting that the ADC decline may not be mediated by voltage-gated sodium influx and glutamate release.
2000 Elsevier Science B.V. All rights reserved.
Theme : Disorders of the nervous system
Topic : Ischemia
Keywords : Diffusion-weighted magnetic resonance imaging; Global cerebral ischemia; Sodium channel blocker
1. Introduction apparent diffusion coefficient ADC of water molecules
correlates with the changes of extracellular water volume During cerebral ischemia, a compromised energy supply
[17,18,21]. Ischemia leads to a decline of the ADC with a in the neurons leads to failure of energy-dependent ion
return to normal values during reperfusion in global [5,10] exchange pumps. This results in anoxic depolarization of
and focal ischemia [22]. Measuring the ADC during cells, a run-down in transmembrane ion gradients, a
ischemia allows for real-time, noninvasive monitoring of massive release of excitatory amino acids EAAs, and a
intra- and extracellular water movements, which may fluid shift from the extracellular to the intracellular com-
result from acute excitotoxicity [9,26]. DWI is therefore partment [29].
considered to be a powerful tool for evaluating ischemic Numerous previous studies have demonstrated that
damage during acute cerebral ischemia, and has been used diffusion-weighted imaging DWI and calculation of the
to assess therapeutic drug effects in several animal models of focal cerebral ischemia [3,6,32,38].
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The ability of lamotrigine, a neuronal Na channel
Corresponding author. Tel.: 11-409-772-1221; fax: 11-409-772-
blocker, to attenuate the release of EAAs has been shown
1224. E-mail address
: mzornowutmb.edu M.H. Zornow.
in vitro [37], and various studies in animal models have
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 3 0 1 2 - 2
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demonstrated the ability of lamotrigine to attenuate EAA neck for the later production of cerebral circulatory arrest.
accumulation in the extracellular space and its resulting At the end of the experiment, the animals were euthanized
excitotoxicity after cerebral ischemia [1,7]. Recently, by increasing the inspired halothane concentration to 5
lamotrigine was shown to improve neurobehavioral and and injecting an intravenous dose of potassium chloride.
histologic outcome following global cerebral ischemia [20].
2.3. Drug administration In the present study, we evaluated the use of an easily
reproducible model of transient global cerebral ischemia in Lamotrigine Glaxo Wellcome Inc, Greenville, NC was
the rabbit. This animal model requires minimal surgical administered intravenously at a dose of 50 mg kg diluted
preparation and allows for single or multiple episodes of in 20 ml of deionized water in the lamotrigine group. This
cerebral ischemia of any desired duration. Using this dose of lamotrigine has been shown to prevent any
model, we investigated the effect of the preischemic increase of glutamate during 10 min of ischemia [1], and
intravenous administration of lamotrigine on ischemia- improved neurobehavioral outcome after a 6.5 min is-
induced cytotoxic brain edema through serial monitoring chemic episode [20]. The drug was infused over 20 min
of the ADC. starting 90 min before the onset of ischemia. The animals
in the control group received an identical volume of deionized water without lamotrigine. The infusion medium
2. Materials and methods was prepared by an investigator not involved in image
