doi:10.1016/j.nbd.2004.09.014 
Copyright © 2004 Elsevier Inc. All rights reserved.
Role of nitric oxide in cerebral blood flow changes during kainate seizures in mice: genetic and pharmacological approaches
Anne Pereira de Vasconcelosa, 
, 
, Viviane Bouillereta, Véronique Ribana, Claude Wasterlainb and Astrid Nehliga
aINSERM U 398, Faculté de Médecine, 67085 Strasbourg Cédex, France
bEpilepsy Research, Veterans Affairs Greater Los Angeles Healthcare System, Department of Neurology and Brain Research Institute, UCLA School of Medicine, Los Angeles, CA, USA
Received 8 July 2004;
revised 6 September 2004;
accepted 28 September 2004.
Available online 8 December 2004.
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Abstract
The role of neuronal nitric oxide (NO) in the cerebrovascular response to partial seizures induced by intrahippocampal injection of kainate (KA) was investigated in mice deleted for the neuronal NO synthase gene (nNOS−/−) and in wild-type controls (WT). A second group of WT mice received the nNOS inhibitor, 7-nitroindazole (WT-7NI). Local cerebral blood flow (LCBF) was measured using the quantitative 14C-iodoantipyrine method. Within the epileptic focus, all three groups of seizing mice (WT, WT-7NI, and nNOS−/−) showed significant 26–88% LCBF increases in ipsilateral hippocampus, compared to saline-injected mice. Contralaterally to the epileptic focus, KA seizures induced a 21–47% LCBF decreases in hippocampus and limbic cortex of WT mice and in most contralateral brain structures of nNOS−/− mice, while WT-7NI mice showed no contralateral CBF change. Neuronal NO appears to be not involved in the cerebrovascular response within the epileptic focus, but may rather have a role in the maintenance of distant LCBF regulation during seizures.
Keywords: Neuronal nitric oxide synthase; Knockout mice; 7-Nitroindazole; Kainate seizures; Intrahippocampal injection; Cerebral blood flow
Fig. 1. Representative electroencephalographic (EEG) activity recorded from frontoparietal cortex in saline- and KA-injected mice. In control conditions (panel A), a 7- to 9-Hz sinusoidal background rhythm was present with no spike-and-wave discharges. At the awakening from anesthesia, KA-induced seizures were characterized by uni- or bilateral spikes and slow waves (representative sections in panels B and C).
Fig. 2. Effects of KA seizures on LCBF within the hippocampus. Values are means ± SD of five to six mice per group. *P < 0.01, statistically significant difference from saline.
Fig. 3. Effects of KA seizures on LCBF outside of the hippocampus. Values are means ± SD of five to six mice per group. *P < 0.01, **P < 0.001, statistically significant differences from saline.
Fig. 4. Representative coronal 14C IAP autoradiograms of mice after KA injection, taken at the level of the ventral hippocampus, dorsal hippocampus (injection site), and striatum. Grain densities reflect variations in regional tissue radioactivity. The radioactive tracer was injected 4–6 h after KA. Note the relatively high tracer level in the ipsilateral dorsal hippocampus, spreading to other ipsilateral areas in nNOS−/− mice. Note also the relatively low radioactive tracer concentration contralaterally in nNOS−/− mice and in the whole brain of WT-7NI mice.
Table 1.
Effects of kainate seizures on physiological variables in WT, WT-7NI, and nNOS−/− mice
Values are means ± SD of five to six animals per group.
* P < 0.01, statistically significant difference from saline condition (Bonferroni's
t test).
Table 2.
Effects of kainate seizures on LCBF in wild-type mice (WT)
Values, expressed as ml/100 g/min, represent means ± SD of the number of animals in parentheses. I = Ipsilateral; C = contralateral.
a P < 0.01, statistically significant difference from saline (Bonferroni's
t test).
* P < 0.01, statistically significant difference from contralateral side (paired Student
t test)
** P < 0.001, statistically significant difference from contralateral side (paired Student
t test).
Table 3.
Effects of kainate seizures on LCBF in nNOS−/− mice
Values, expressed as ml/100 g/min, represent means ± SD of the number of animals in parentheses. I = Ipsilateral; C = contralateral.
a P < 0.01, statistically significant difference from saline (Bonferroni's
t test).
b P < 0.001, statistically significant difference from saline (Bonferroni's
t test).
* P < 0.01, statistically significant difference from contralateral side (paired Student
t test).
** P < 0.001, statistically significant difference from contralateral side (paired Student
t test).
Table 4.
Effects of kainate seizures on LCBF in 7-nitroindazole-treated mice (WT-7NI)
Values, expressed as ml/100 g/min, represent means ± SD of the number of animals in parentheses. I = Ipsilateral; C = contralateral.
* P < 0.01, statistically significant difference from contralateral side (paired Student
t test).
a P < 0.01, statistically significant difference from saline (Bonferroni's
t test).
Abstract
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