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Infection and Immunity, December 1999, p. 6364-6368, Vol. 67, No. 12
Felsenstein Medical Research
Center1 and Schneider Children's
Medical Center of Israel,
Received 9 July 1999/Returned for modification 27 August
1999/Accepted 30 September 1999
Convulsions and encephalopathy are frequent complications of
childhood shigellosis. We studied the role of nitric oxide (NO) in
Shigella-related seizures in an animal model. Pretreatment of mice with Shigella dysenteriae 60R sonicate elevated
serum NO levels and enhanced the convulsive response to
pentylenetetrazole (PTZ), as indicated by a higher mean convulsion
score and a higher number of mice responding with seizures. Treatment
of the mice with S-methylisothiourea sulfate (SMT), a
potent inhibitor of inducible NO synthase (NOS), prevented the
elevation of serum NO levels and concomitantly reduced the enhanced
response to PTZ. The mean convulsion scores were 0.7, 0.7, 1.3, and 0.8 for mice treated with saline, saline and SMT, S. dysenteriae 60R sonicate, and S. dysenteriae
60R sonicate with SMT, respectively (P = 0.001 for 60R
sonicate versus saline and P = 0.013 for 60R sonicate versus 60R sonicate with SMT). The corresponding seizure rates were 40, 44, 75, and 47% for saline, saline with SMT, S. dysenteriae 60R sonicate, and S. dysenteriae 60R
sonicate with SMT, respectively (P = 0.0004 for 60R sonicate versus saline and P = 0.005 for 60R sonicate versus 60R sonicate with SMT). In contrast,
injection of N-nitro-L-arginine, a selective
inhibitor of constitutive NOS, neither abolished the elevation of serum
NO nor attenuated the enhancement of seizures. These findings indicate
that NO, induced by S. dysenteriae 60R sonicate, is
involved in enhancing the susceptibility to seizures caused by S. dysenteriae.
Shigellosis, the acute
gastroenteritis caused by Shigella species, is often
accompanied by neurologic complications (1, 2, 5). The most
frequent complications are convulsions and encephalopathy, which can be
fulminant, leading rapidly to unconsciousness and death
(11). Typically, the neurologic disorders appear very early
in the course of the disease, often before the onset of diarrhea
(2, 11). Neurologic complications have also been reported in
infections caused by certain enterohemorrhagic Escherichia coli strains (14, 17).
The pathogenesis of Shigella- and E. coli-associated neurologic disturbances is unclear. Shiga toxin
(ST), the main toxic product of Shigella dysenteriae, and
two very similar toxins, Shiga-like toxins (SLTs) 1 and 2, produced by
certain E. coli strains (for review, see reference
24), have been implicated because of their
neurotoxicity in laboratory animals (3, 4, 7, 8, 15, 27).
Recent data indicate that lipopolysaccharide (LPS) acts in concert with
ST and SLTs in pathological processes. Barrett et al. showed that the
toxicity of SLT in mice was macrophage dependent (3) and
that LPS either increased or decreased SLT toxicity in mice and rabbits
depending on the time of its application (4). In a
comparison of LPS-responding and LPS-nonresponding mice infected with
either SLT-producer or SLT-nonproducer E. coli strains,
Karpman et al. observed the most severe systemic manifestations in the LPS-responding mice inoculated with SLT-producing E. coli
(17).
Our team, using a model of pentylenetetrazole (PTZ)-induced seizures,
had previously shown that preinjection of mice with crude preparations
of S. dysenteriae 60R (a producer of ST) or with E. coli H-30 (a producer of SLT) reduced the threshold to PTZ-induced
seizures (34). The increased sensitivity to PTZ could be
mimicked by pretreating the mice with ST together with LPS, but not
with either of them alone (34). Employing this model, we
have further demonstrated that tumor necrosis factor alpha (TNF- LPS, TNF- NO is produced in many cell types and organs by NO synthases (NOSs),
which convert L-arginine to L-citrulline and
NO. There are two types of NOSs: a constitutive NOS (cNOS), which is
regulated by changes in intracellular calcium; and an inducible NOS
(iNOS), which is stimulated during infection and inflammatory processes (21). Both types are present in the brain: in endothelial
cells and certain neurons, NO is catalyzed by constitutive endothelial or brain NOSs, and in microglia and astrocytes, it is catalyzed by iNOS
in response to LPS, IL-1 Results of studies on the role of NO in convulsions have been
contradictory, indicating either anticonvulsive or proconvulsive activity, depending on the model employed (18, 29).
These studies examined the role of NO produced by cNOS,
but not under conditions in which increased NO levels are
achieved by stimulation of iNOS.
In the present study, we employed the PTZ-induced seizure model to
investigate the role of NO induced by S. dysenteriae in the
enhanced susceptibility to seizures after S. dysenteriae
administration shown in our previous study (34).
(This work was presented in part at the 39th Interscience Conference on
Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September
1999.)
Mice.
ICR outbred male mice 25 to 28 days old (20 to 25 g) were maintained under standard conditions.
Materials.
PTZ, S-methylisothiourea sulfate
(SMT), N-nitro-L-arginine (NNA), and
flavin adenine dinucleotide disodium salt (FAD) were purchased from
Sigma Chemical Co. (St. Louis, Mo.). Aspergillus nitrate
reductase, NADPH, lactate dehydrogenase (LDH [bovine muscle]), and
pyruvic acid sodium salt were purchased from Boehringer (Mannheim, Germany).
Preparation of bacterial sonicate.
Strain 60R of S. dysenteriae serotype 1 was grown in syncase broth for 48 h
with shaking, lysed by sonication, and filter sterilized as described
previously (26). The bacterial sonicate was analyzed for
protein content, cytotoxic activity, and lethality in mice
(34).
PTZ-induced convulsion.
Induction of seizures with PTZ was
performed as described previously (34). Groups of six to
eight mice were inoculated intraperitoneally (i.p.) with PTZ (50 mg/kg
of body weight) and observed for their reaction for 10 min. The
reaction included several phases: unresponsiveness, mild contractions,
clonic seizures, and tonic seizures (forelegs and then hind legs
rigidly extended to the rear), occasionally followed by death. For
statistical analysis, each phase was given a numeric score
(23): unresponsiveness = 0, mild contractions = 1, clonic seizures = 2, tonic seizures = 3, and death = 4. The response of each mouse was scored according to the highest phase reached, and a mean seizure severity score was calculated for each group.
Enhancement of PTZ-induced seizures.
Groups of six to eight
mice were inoculated with 1,000 50% cytotoxic doses (~4 50% lethal
doses [LD50]) of S. dysenteriae 60R sonicate.
Saline-treated mice were used as controls. At 7 h after injection,
the mice were inoculated with PTZ (50 mg/kg) and scored for their
response compared with that of controls (33, 34).
NO measurement.
An indirect determination of NO was
performed by measuring the combined amounts of the stable products of
NO, nitrite (NO2), and nitrate (NO3), in the
mouse serum. Nitrate was first reduced to nitrite by using
Aspergillus nitrate reductase, according to the procedure
previously described (13). Nitrite levels were then
determined by a colorimetric method whereby equal volumes of sample
serum and Griess reagent (1% sulfanilamide and 0.1% naphthyl-ethylenediamine in 2% H3PO4) were
mixed. The A540 was measured, and nitrite
concentrations were calculated from a standard curve of
NaNO2.
Treatment with NOS inhibitors.
SMT was injected i.p. at a
dose of 2.0 mg/kg of body weight. Groups of six to eight mice were
injected with S. dysenteriae 60R sonicate or saline and
subsequently treated with SMT or saline 2 h later. At 5 h
after injection of SMT (or saline), the mice were treated with PTZ and
scored for their response, as described above. NNA was injected i.p. at
a dose of 2.5 mg/kg of body weight. Groups of six to eight mice
preinjected with S. dysenteriae 60R sonicate or saline were
treated with NNA or saline 3, 5, and 6.5 h later. At 30 min after
injection of the final NNA (or saline) dose, the mice were treated with
PTZ, as described above.
Statistical analysis.
The difference in the incidence of
seizures among the various groups in each experiment was analyzed by
chi-square test for multiple comparisons or by Fisher's exact test, as
appropriate. Convulsion scores were compared by two-tailed unpaired
t test or one-way analysis of variance, as appropriate.
Induction of NO production by S. dysenteriae 60R
sonicate.
An i.p. injection of S. dysenteriae 60R
sonicate rapidly induced NO in mouse circulation. An increase in the
concentration of the two stable products of NO,
NO Inhibition of NO production by inhibitors of NOSs.
Production of NO in response to S. dysenteriae 60R
sonicate was inhibited by injection of the potent iNOS inhibitor SMT
(31) (2 mg/kg) 2 h after bacterial
administration. The mean ± SE serum NO levels 7 h after 60R
sonicate injection were 150 ± 25, 90 ± 13, 535 ± 15, and 90 ± 15 µM for mice treated with saline alone, saline with
SMT, 60R sonicate with saline, or 60R sonicate followed by SMT,
respectively (P = 0.001 for 60R sonicate versus saline, and P = 0.0001 for 60R sonicate versus 60R sonicate
with SMT) (Fig. 2A). There was no similar
significant reduction of NO production following treatment with the
highly selective brain and endothelial cNOS inhibitor NNA
(22) (2.5 mg/kg) (Fig. 2B).
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Role of Nitric Oxide in the Enhancement of
Pentylenetetrazole-Induced Seizures Caused by Shigella
dysenteriae
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
)
and interleukin-1
(IL-1) play an important role in the enhanced
seizure response of mice to PTZ after administration of S. dysenteriae (33).
, and IL-1 themselves (12, 30), as well as
ST, as we had shown previously (32), induce another host
mediator
nitric oxide (NO). NO is well recognized as an important
messenger in the peripheral and central nervous systems (6,
10). In the brain, NO plays an essential role in the control of
blood flow. As an excitatory neurotransmitter involved in synaptic
plasticity, it influences complex neural functions, such as brain
development, memory formation, and behavior. Overproduction of NO,
however, has been linked to neurotoxicity during ischemia, some forms
of neurodegenerative brain diseases, and induction of seizures
(10).
, and gamma interferon (9, 19).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
2 and NO3, was
detectable 3 h after injection, peaking at 5 h and returning to baseline levels at 24 h (Fig. 1).
The mean ± standard error (SE) serum NO levels 1, 3, 5, 8, and
24 h after 60R sonicate administration were 88 ± 10, 141 ± 46, 650 ± 218, 167 ± 29, and 63 ± 47 µM, respectively.
View larger version (10K):
[in a new window]
FIG. 1.
Serum NO production in response to S. dysenteriae 60R sonicate (4 LD50 i.p.). Measurement of
the stable products of NO, NO 2, and
NO3, was performed by using nitrate reductase
and the colorimetric assay with Griess reagent, as described in
Materials and Methods. Each point represents the average of three
animals.
View larger version (54K):
[in a new window]
FIG. 2.
Effect of treatment with NOS inhibitors on serum NO
levels 7 h after S. dysenteriae administration. Mice
were injected (i.p.) with saline alone, saline with NOS inhibitor,
S. dysenteriae 60R sonicate with saline, or S. dysenteriae 60R sonicate with NOS inhibitor. Each point represents
the mean of five determinations. (A) Mice treated with SMT.
P = 0.001 for S. dysenteriae sonicate versus
saline and P = 0.0001 for S. dysenteriae
sonicate versus S. dysenteriae sonicate with SMT. SMT (2 mg/kg) was administered 2 h after S. dysenteriae
sonicate. (B) Mice treated with NNA. P = 0.0001 for
S. dysenteriae sonicate versus saline and is nonsignificant
for S. dysenteriae sonicate versus S. dysenteriae
sonicate with NNA-treated mice. NNA (2.5 mg/kg) was administered 3, 5, and 6 1/2 h after S. dysenteriae 60R sonicate.
Effect of NOS inhibitors on enhancement of PTZ-induced seizures by S. dysenteriae. Pretreatment of mice with S. dysenteriae 60R sonicate enhanced the seizure response to PTZ as early as 7 h after administration. This was indicated by a higher mean convulsion score (Fig. 3) as an indication of the severity of seizures and a higher number of mice responding with seizures compared with control (saline-pretreated) mice (Table 1).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Our data show that treatment of mice with the iNOS inhibitor SMT completely prevents the elevation of NO levels in serum after S. dysenteriae sonicate administration and concomitantly reduces the enhanced response to PTZ. In contrast, NNA, an inhibitor of brain and endothelial cNOS, neither abolished the induction of NO nor attenuated the PTZ enhancement of the seizures. These findings strongly imply that NO, which is induced by exposure to the S. dysenteriae 60R sonicate, plays an important role in the sensitization of the central nervous system to convulsive activity.
NO has been linked to epileptic activity through the formation of cyclic GMP (cGMP). Stimulation of the brain N-methyl-D-aspartate (NMDA) receptors with glutamate or excitatory amino acids increases calcium influx, which results in activation of cNOS and formation of NO. NO in turn activates guanylate cyclase to synthesize cGMP, which is assumed to initiate seizures (10).
NO modulates experimentally induced seizures in a complex manner. In
addition to stimulation of cGMP, NO has several other actions: it
blocks NMDA receptors in a negative feedback manner, thereby
attenuating excitable activity (20); promotes and suppresses glutamate release (25); and reduces the receptor activity of the inhibitory 
-aminobutyric acid (GABA) neurotransmitter
(28). PTZ induction of seizures may be related to the
antagonistic activity of the compound at the GABA-A receptor and to
its activation of the NMDA receptor (16). Thus, the induced
NO may augment the capability of PTZ to induce seizures at both pathways.
The various investigations of the role of NO in epileptic activity employed mainly proconvulsive drugs and inhibitors of NOS. The results were contradictory, indicating both an anticonvulsive role and a proconvulsive role of NO, depending on the model used (18, 29). Some of the authors postulated that multiple factors, such as the specific proconvulsive drug, the type of NOS inhibitor, their concentrations, mode of application, and specific strain or species used, affect the results. These studies, however, evaluated the involvement of NO produced by cNOS during epileptic activity. To the best of our knowledge, ours is the first study to demonstrate a role for NO produced by iNOS in the induction of seizures.
We found that NO induced by S. dysenteriae sonicate is proconvulsive. However, the relevance of S. dysenteriae-induced NO elevation to other infectious diseases associated with seizures is as yet unclear. In our previous study, we found that the enhancement of seizures is a result of mutual actions of ST and LPS. Injection of LPS alone, which also induced high levels of NO, was not sufficient for a significant increase in convulsion rates (34). Thus, it is possible that like in earlier studies of cNOS-produced NO in seizure modulation, which had different results according to the model used, the exact role of NO produced by iNOS is determined by the nature of the infection. Multiple factors, such as the specific pathological processes, the interaction of NO with other induced factors, and the amount or site of NO release, may all determine whether NO is proconvulsive or anticonvulsive.
The exact mode of interaction between ST and LPS that renders the central nervous system vulnerable to convulsive activity is unclear. Our results showed that their activity is at least partly mediated by NO induction. ST is transported very rapidly to the central nervous system, where it binds to endothelial and neuron cells and exerts cytotoxic activity (7, 8, 27). We speculate that NO, which is itself neurotoxic, not only modulates seizures in various mechanisms, but may also augment cell damage.
In conclusion, using the PTZ-induced seizure mouse model, we have shown that NO, which is induced by S. dysenteriae, plays a proconvulsive role in the process that leads to the enhancement of PTZ-induced seizures caused by administration of S. dysenteriae. Similar mechanisms may be involved in the neurologic manifestations of human shigellosis, enterohemorrhagic E. coli infection, and possibly other infectious diseases.
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ACKNOWLEDGMENTS |
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We thank Charlotte Sachs and Gloria Ginzach of the Editorial Board, Rabin Medical Center, Beilinson Campus, for assistance.
This study was supported by Tel Aviv University Research Foundation grant 572/96.
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FOOTNOTES |
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* Corresponding author. Mailing address: Unit of Infectious Diseases, Schneider Children's Medical Center of Israel, P.O. Box 8145, Petah Tiqva 49181, Israel. Phone: 972-3-925 3680/3837. Fax: 972-3-925 3056. E-mail: ashai{at}post.tau.ac.il.
Editor: E. I. Tuomanen
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REFERENCES |
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Discussion
References
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Infection and Immunity, December 1999, p. 6364-6368, Vol. 67, No. 12
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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