Nitric oxide mediates the increase in local cerebral blood flow during focal seizures.

Vasconcelos, Anne Pereira de; Baldwin, Roger A.; Wasterlain, Claude G.

doi:10.1073/pnas.92.8.3175

Cited by 43 publications

(17 citation statements)

References 43 publications

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“…Nitric oxide in epilepsy might contribute to an anticonvulsant effect) during KA-induced seizures in rats, there is increased severity of seizures accompanied by decreased hippocampal blood flow preceeding mortality (Rigaud-Monet et al, 1994;1995) consistent with the findings of Haberney et al (1992), Penix et al (1994), and Maggio et al (1995). Furthermore, focal administration of bicuculline induces cortical hyperaemia accompanying seizures which are inhibited by L-NOARG, but seizure propensity is unaffected (Pereira-de-Vasconcelos et al, 1995), suggesting that NO mediates vascular responses during seizures, although results with systemic administration of L-NOARG are less supportive of this hypothesis (Wang et al, 1994;Theard et al, 1995) Many results, however, support a convulsant role for NO in epilepsy: kindling produces a long-lasting increase in NO synthase activity (Al-Ghoul et al, 1995). Direct administration of NO 330-800 ymol into the brain of rats has been attempted resulting in brief tonic convulsive episodes (Smith et al, 1991).…”

Section: Locomotor Performance In Gep Ratssupporting

confidence: 80%

Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Smith

Man

Yip

et al. 1996

British J Pharmacology

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To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound‐induced seizures in DBA/2 mice and in genetically epilepsy‐prone (GEP) rats. The neuronal selective nitric oxide synthase inhibitor, 7‐nitroindazole (7‐NI) is anticonvulsant in these models with ED50 values against clonic seizures in mg kg−1 i.p. (times following injection) of: 74 (+0.25 h), 120 (+1 h) in DBA/2 mice, and 56 (+0.25 h), 42 (+0.5 h), 36 (+1 h), 28 (+2 h), 38 (+4 h), 93 (+8 h) in GEP rats. Therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) for 7‐NI are low, ranging from 0.6 to 1.1 at +0.25 h to +1 h after administration in GEP rats, but are more favourable at later times (1.6 at +2 h and 2.9 at +4 h). The substrate for nitric oxide synthase, L‐arginine (500–5000 mg kg−1, i.p. or 100–300 μg, i.c.v.) but not D‐arginine (300 μg i.c.v.) is anticonvulsant in DBA/2 mice. L‐Arginine (500–5000 mg kg−1, i.p. or 1800–6000 μg, i.c.v.) is a more potent anticonvulsant than D‐arginine (1500–2500 mg kg−1, i.p. or 6000 μg, i.c.v.) in GEP rats. In DBA/2 mice, L‐arginine (30 μg i.c.v.) reverses the anticonvulsant effect of 7‐NI (50 mg kg−1, i.p.). In GEP rats, low dose L‐arginine (25–50 mg kg−1, i.p.) but not D‐arginine (50 mg kg−1, i.p.) reverses the anticonvulsant effect of low dose 7‐NI (25 mg kg−1, i.p.). A higher dose of L‐arginine (500 mg kg−1, i.p.) or 7‐NI (50 mg kg−1, i.p.) produces summation of anticonvulsant effect. The product for nitric oxide synthase, L‐citrulline (250–831 μg i.c.v.), is convulsant in DBA/2 mice. The anticonvulsant effect of the neuronal selective nitric oxide synthase inhibitor, 7‐nitroindazole, may therefore be mediated by L‐arginine accumulation, as well as by a reduction in nitric oxide and L‐citrulline formation in rodent models of reflex epilepsy.

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Section: Locomotor Performance In Gep Ratssupporting

confidence: 80%

Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Smith

Man

Yip

et al. 1996

British J Pharmacology

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“…Unexpectedly, eNOS was not detectable in the present study, despite the fact that eNOS appears to be responsible for NO that mediates an increase in local cerebral blood flow during focal seizures (10). However, eNOS may be detected at higher protein concentrations.…”

Section: Discussioncontrasting

confidence: 46%

“…In addition, NO, identified as an endothelium-derived relaxing factor (9), is a potent vasodilator that regulates cerebral blood flow in basal conditions and during certain types of neuronal activation, including seizures (10).…”

mentioning

confidence: 99%

Role of Nitric Oxide in the Epileptogenesis of EL Mice

2000

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Summary:Purpose: To understand the role of nitric oxide (NO) in the regulation of seizures, we measured the extracellular levels of the NO metabolites nitrite and nitrate as indices of NO generation in the parietal cortex, hippocampus, and temporal cortex of EL mice. Furthermore, alterations of neuronal, endothelial, and inducible nitric oxide synthetase (nNOS, eNOS, and iNOS, respectively) were observed to correlate them with epileptogenesis.Methods: EL mice of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used. Nitrite was quantified using the specific absorbancy of diazo dye. NOS isoenzymes (nNOS, iNOS, and eNOS) were also investigated in the hippocampus during development until mice were 30 weeks old. Samples (total protein, 8.33 to 8.43 Fg) were separated by sodium dodecyl sulfate-polyacrylamide geI electrophoresis and identified by immunoblotting.Results: EL mice that experienced repetitive seizures showed a remarkable increase in nitrite in the hippocampus at 30 weeks of age compared with EL mice that had no experience of seizures. nNOS and iNOS were major and minor components, respectively, and both increased in parallel with the development of epileptogenesis. eNOS was not detectable.Conclusions: Excess iNOS (and subsequent increase in harmful NO) and deficient eNOS (and subsequent decrease in NO identified as an endothelium-derived relaxing factor) may work together to form a focus complex. Key Words: Epileptic mutant-EL mouse-Nitric oxide (NO)-Nitric oxide synthetase (NOS)-Abnormal plasticity-Epileptogenesis.The EL mouse is an inbred mutant strain that has been used as an animal model of secondarily generalized seizures (1,2). Several lines of evidence indicate that seizure discharges are initiated in the parietal area and then generalized through the hippocampus (3). These findings have been substantiated by histochemical and biochemical analyses of glucose utilization (4) and inhibitory neurotransmissions by aminobutyric acid (5). The developmental formation of the focus complex, which consists mainly of the parietal cortex and the hippocampus, has been hypothesized to be key to epileptogenesis in EL mice.In our recent studies, allopurinol, a xanthine oxidase inhibitor, exerted an antiepileptic action on EL mice (6), and the drug ameliorated abnormalities in the activities of the free radical scavenger superoxide dismutase isoenzymes, which are present in the hippocampus (7). Furthermore, DNA fragmentation was found in the hippocampal CA1 region and the parietal cortex in EL mice, presumably as a consequence of the production of free radicals attributable to decreased Cu,Zn-superoxide dismutase (7). Nitric oxide (NO) has been identified as a source of free radical oxidants with special relevance to pathological conditions in the brain, and reactive nitrogen intermediates could damage DNA as an important target (8). In addition, NO, identified as an endothelium-derived relaxing factor (9), is a potent vasodilator that regulates cerebral blo...

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“…Based on our observations, we cannot exclude that additional mechanisms could be involved in mediating the inhibitory effects of L-NAME on Mg 2+ -free-induced epileptogenesis. For example, there is evidence supporting a NO-mediated increase in cerebral blood flow (CBF) during bicucullineinduced seizures (Pereira de Vasconcelos et al 1995) and neuronal (Dirnagl et al 1993) or NMDA receptor activation (Faraci and Breese 1993). However, whether NO mediates the CBF increase occurring during functional brain activation remains a controversial issue, with NO synthase inhibitors being found to either attenuate (Pereira de Vasconcelos et al 1995) or have no effects (Wang et al 1993) on the CBF changes associated with increased neuronal activity (i.e.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of nitric oxide synthase prevents magnesium-free-induced epileptiform activity in guinea-pig piriform cortex neurones in vitro

Libri

Santarelli

Nisticò

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, were examined on Mg2+-free-induced epileptiform activity, in guinea-pig piriform cortex slices in vitro. L-NAME (0.1-1 mM) had no effect on neuronal membrane properties or electrically-evoked postsynaptic potentials (PSPs). In contrast, during superfusion of the slices with Mg2+-free solution neurones exhibited spontaneous and stimulus-evoked epileptiform potentials that were suppressed in the presence of L-NAME (100 microM) or the selective NMDA receptor antagonist DL-APV (100 microM). The inhibitory effects induced by L-NAME were reversibly reduced by L-arginine (1 mM), but not D-arginine (1 mM), the latter drug not being a substrate for NO formation. It was concluded that L-NAME can suppress epileptiform activity induced by Mg2+-free exposure primarily through a decrease in presynaptic transmitter release, although additional actions on the NMDA-receptor complex were also considered.

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Nitric oxide mediates the increase in local cerebral blood flow during focal seizures.

Cited by 43 publications

References 43 publications

Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Inhibition of nitric oxide synthase prevents magnesium-free-induced epileptiform activity in guinea-pig piriform cortex neurones in vitro

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