 |
 Previous Article
The Journal of Neuroscience, November 15, 1998, 18(22):9564-9571
Attenuated Neurotransmitter Release and Spreading Depression-Like
Depolarizations after Focal Ischemia in Mutant Mice with Disrupted Type
I Nitric Oxide Synthase Gene
Masao
Shimizu-Sasamata2,
Prince
Bosque-Hamilton1,
Paul L.
Huang3,
Michael A.
Moskowitz2, and
Eng H.
Lo1
1 Neuroprotection Research Laboratory, Departments of
Neurology and Radiology, 2 Stroke and Neurovascular
Regulation Laboratory, Departments of Neurosurgery and Neurology, and
3 Cardiovascular Research Center, Department of Medicine,
Massachusetts General Hospital, Harvard Medical School, Charlestown,
Massachusetts 02129
Nitric oxide (NO) plays a complex role in the pathophysiology of
cerebral ischemia. In this study, mutant mice with disrupted type I
(neuronal) NO synthase (nNOS) were compared with wild-type littermates
after permanent focal ischemia. Cerebral blood flow in the central and
peripheral zones of the ischemic distribution were measured with laser
doppler flowmetry. Simultaneously, microdialysis electrodes were used
to measure extracellular amino acid concentrations and DC potential in
these same locations. Blood flow was reduced to <25 and 60% of
baseline levels in the central and peripheral zones, respectively;
there were no differences in nNOS mutants versus wild-type mice. Within
the central ischemic zone, DC potentials rapidly shifted to  20 mV in
all mice. In the ischemic periphery, spreading depression (SD)-like
waves of depolarization were observed. SD-like events were
significantly fewer in the nNOS mutant mice. Concurrent with these
hemodynamic and electrophysiological perturbations, extracellular
elevations in amino acids occurred after ischemia. There were no
detectable differences between wild-type and mutant mice in the
ischemic periphery. However, in the central zone of ischemia,
elevations in glutamate and GABA were significantly lower in the nNOS
mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were
significantly smaller than in their wild-type littermates. Overall, the
number of SD-like depolarizations and the integrated efflux of
glutamate were significantly correlated with infarct size. These
results suggest that NO derived from the nNOS isoform contributes to
tissue damage after focal ischemia by amplifying excitotoxic amino acid
release in the core and deleterious waves of SD-like depolarizations in
the periphery.
Key words:
ischemia; excitotoxicity; knock-out mice; microdialysis; NO; spreading depression
Copyright © 1998 Society for Neuroscience 0270-6474/98/18229564-08$05.00/0
This article has been cited by other articles:
|
|
|
|
 
M. Oda, S. Kure, T. Sugawara, S. Yamaguchi, K. Kojima, T. Shinka, K. Sato, A. Narisawa, Y. Aoki, Y. Matsubara, et al.
Direct Correlation Between Ischemic Injury and Extracellular Glycine Concentration in Mice With Genetically Altered Activities of the Glycine Cleavage Multienzyme System
Stroke,
July 1, 2007;
38(7):
2157 - 2164.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. R. Madamanchi, A. Vendrov, and M. S. Runge
Oxidative Stress and Vascular Disease
Arterioscler Thromb Vasc Biol,
January 1, 2005;
25(1):
29 - 38.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. G. Somjen
Mechanisms of Spreading Depression and Hypoxic Spreading Depression-Like Depolarization
Physiol Rev,
July 1, 2001;
81(3):
1065 - 1096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Iwase, K. Miyanaka, A. Shimizu, A. Nagasaki, T. Gotoh, M. Mori, and M. Takiguchi
Induction of Endothelial Nitric-oxide Synthase in Rat Brain Astrocytes by Systemic Lipopolysaccharide Treatment
J. Biol. Chem.,
April 14, 2000;
275(16):
11929 - 11933.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. HUANG, A. SHENOY, J. CUI, W. HUANG, and P. K. LIU
In situ detection of AP sites and DNA strand breaks bearing 3'-phosphate termini in ischemic mouse brain
FASEB J,
February 1, 2000;
14(2):
407 - 417.
[Abstract]
[Full Text]
|
|
|
|
