Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuronal isoform of nitric oxide synthase (nNOS), a NADPH-dependent diaphorase, is considered to play a role in motoneuron death induced by sciatic nerve transection in neonatal rats. Neuronal loss in these circumstances has been correlated with nitric oxide (NO) production and NADPH-diaphorase positivity in motoneurons after axotomy. In the present study we looked for a possible protective effect of melatonin, an antioxidant agent and inhibitor of nNOS, on spinal motoneurons after axonal injury. Neonatal Wistar rats (P2) were submitted to sciatic nerve transection and allowed to survive to P7. Melatonin at doses of 1, 5, 10, 50 and 100 mg/kg was given subcutaneously before and at intervals after the surgery. Controls operated in the same way received dilution vehicle or no treatment. The animals were killed by perfusion of fixative and the spinal cord was examined in serial paraffin sections. The motoneurons of the sciatic pool were counted in the axotomized and contralateral sides. Immunohistochemistry for nNOS and glial fibrillary acidic protein was used to evaluate nNOS expression in the axotomized cells and the astrocytic response. We found that melatonin at doses of 1-50 mg/kg decreased neuronal death. Astrocytic hypertrophy in melatonin treated animals was less intense. There were no differences in nNOS expression between treated and control rats, and surviving motoneurons of the sciatic pool did not express the enzyme, suggesting that nNOS may not be involved in neuronal death or survival in these experimental conditions. Possible mechanisms of melatonin neuroprotection, which was equally effective at doses of 1-50 mg/kg, are discussed. Doses of 50 and 100 mg/kg caused failure to thrive, seizures or death. The fact that neuroprotective doses were far smaller than toxic ones should encourage testing of melatonin in neurologic diseases.
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PMID:Neuroprotective action of melatonin on neonatal rat motoneurons after sciatic nerve transection. 1181 4

Acute subcutaneous administration of lower doses of morphine (0.5, 1 and 3 mg/kg) increase the threshold of seizures induced by pentylenetetrazole (PTZ) in mice, whereas higher doses of morphine (15, 30 and 60 mg/kg) have proconvulsant effects. The effect of systemic administration of nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NNA) and nitric oxide synthase (NOS) L-arginine on biphasic effect of morphine was investigated. Acute administration of both L-NAME (1, 3 and 10 mg/kg) and L-NNA (1 and 10 mg/kg) as well as chronic pretreatment with L-NAME (1 and 10 mg/kg, 4 days) dose-dependently inhibited both the anticonvulsant and proconvulsant effects of morphine (1 and 30 mg/kg, respectively). The inhibition was complete for anticonvulsant effect while partial for proconvulsant effect. L-arginine at doses that did not affect seizure threshold per se (acute, 30 and 60 mg/kg; chronic, 60 mg/kg) potentiated both anticonvulsant and proconvulsant properties of less potent doses of morphine (0.5 and 15 mg/kg, respectively). The L-arginine induced potentiation of both phases of morphine effect was blocked by L-NAME (0.5-30 mg/kg). Moreover, low and per se non-effective doses of naloxone (0.1 mg/kg) and L-NAME (0.3, 0.5 or 1 mg/kg) showed additive effects in inhibiting both phases of morphine effects. These results support the involvement of L-arginine/nitric oxide pathway in the modulation of seizure threshold by morphine.
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PMID:The role of nitric oxide in anticonvulsant and proconvulsant effects of morphine in mice. 1182 8

Molsidomine (25 mg kg(-1)), a donor of nitric oxide, commonly used in the treatment of coronary artery disease, enhanced the protective activity of valproate against the clonic phase of pentylenetetrazole-induced seizures in mice, significantly reducing the ED(50) of valproate from 123.5 to 78 mg kg(-1). Molsidomine was found to be ineffective with respect to the protective action of clonazepam, ethosuximide and phenobarbital. Alone, molsidomine in a dose of 25 mg kg(-1) was ineffective in this model of seizures. Since N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthase, failed to reverse the effect of molsidomine on valproate, an involvement of nitric oxide in the mechanism of the anticonvulsive efficacy of valproate does not seem to be probable. Molsidomine (25 mg kg(-1)) significantly elevated the free plasma level of valproate from 33.8 to 46.2 microg ml(-1). Therefore, we conclude that the interaction of molsidomine with valproate is at the pharmacokinetic level. The combination of valproate with molsidomine appears beneficial because is free from adverse effects, in terms of motor impairment and long-term memory deficit. Our results suggest that the dosage of valproate in patients with coronary artery disease treated with molsidomine should be decreased. It would allow us to reduce adverse effects of valproate.
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PMID:Molsidomine enhances the protective activity of valproate against pentylenetetrazole-induced seizures in mice. 1195 65

The effect of nitric oxide synthase (NOS) inhibitors on the brain production of endogenous glutamate receptor antagonist, kynurenic acid, was estimated in vitro. Under standard incubation conditions N(G)-nitro-L-arginine, but not N(G)-nitro-L-arginine methyl ester, up to 5 mM, or 7-nitroindazole, up to 100 microM, inhibited de novo synthesis of kynurenic acid in cortical slices. However, during prolonged incubation, N(G)-nitro-L-arginine methyl ester also reduced the production of kynurenic acid. The substrate for NOS, L-arginine (up to 5 mM), did not influence kynurenic acid synthesis and did not reverse the N(G)-nitro-L-arginine-evoked changes, suggesting that the observed effects are not related to disturbed generation of NO. Enzymatic studies revealed that N(G)-nitro-L-arginine and its methyl ester blocked the activity of brain kynurenine aminotransferase (KAT) I. The activity of KAT II was diminished only by N(G)-nitro-L-arginine. Kinetic analyses have shown that N(G)-nitro-L-arginine and its methyl ester reduce Vmax and increase Km of KAT I, whereas N(G)-nitro-L-arginine diminishes Vmax of KAT II. In conclusion, we report that N(G)-nitro-L-arginine and its methyl ester impair brain synthesis of kynurenic acid, probably via NO-independent mechanism, what could contribute, at least partially, to the enhancement of neurotoxicity or seizures observed in some experimental designs based on their use.
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PMID:N(G)-nitro-L-arginine and its methyl ester inhibit brain synthesis of kynurenic acid possibly via nitric oxide-independent mechanism. 1198 33

The involvement of endogenous opioids and nitric oxide (NO) in the anticonvulsant effects of stress against pentylenetetrazole (PTZ)- or electroconvulsive shock-induced seizures was assessed in mice. The prolonged and intermittent foot-shock stress, which induced opioid-mediated analgesia, had significant protective effects against both seizure types which was reversible by naloxone (0.3, 1 or 2 mg/kg), while brief and continuous foot-shock did not alter the seizure susceptibility. Pre-treatment with non-specific nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 1, 2, 5, 10 or 30 mg/kg), but not with specific inducible NOS (iNOS) inhibitor, aminoguanidine (50 or 100 mg/kg), blocked the stress-induced anticonvulsant effects. The lower doses of naloxone (0.3 mg/kg) and L-NAME (2 mg/kg) showed additive effects in blocking the stress-induced anticonvulsant properties. L-arginine at a per se non-effective dose of 20 mg/kg potentiated the stress-induced anticonvulsant properties, an effect which was inhibited by L-NAME but not by aminoguanidine. Furthermore, a low dose of morphine (0.5 mg/kg) showed potentiation with stress in increasing PTZ seizure threshold. This potentiation was reversed by either naloxone or L-NAME at low doses but not by aminoguanidine. Taken together, these results show that NO synthesis, through constitutive but not iNOS, is involved in opioid-dependent stress-induced anticonvulsant effects against electrical and PTZ-induced convulsions.
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PMID:The involvement of endogenous opioids and nitricoxidergic pathway in the anticonvulsant effects of foot-shock stress in mice. 1204 1

Data about the role of nitric oxide (NO) in epileptogenesis are contradictory. It is found to exert both proconvulsant and anticonvulsant effects. In an attempt to elucidate the role of NO in seizures, male Wistar rats were treated intraperitoneally by pentylenetetrazol (PTZ) (60, 80, and 100 mg/kg) and by a nitric oxide synthase antagonist, N-omega-nitro-L-arginine-methyl-ester (L-NAME) (10, 40, and 70 mg/kg), applied before PTZ. The time to onset and incidence of forelimb dystonia (FLD), generalized clonic convulsions (GCC), clonic-tonic convulsions (CTC), and mortality were recorded. The most successful convulsive response and mortality prevention were found in PTZ (80 mg/kg)-treated groups, where L-NAME (70 mg/kg) decreased the incidence by 29, 50, 67 (p = 0.052), and 50%, respectively, and significantly prolonged the time to onset, except that for mortality. Unexpectedly, L-NAME (40 mg/kg) increased incidence of GCC and mortality by 16%, similar to L-NAME (10 mg/kg) in PTZ (60 mg/kg)-treated groups, where GCC, CTC, and mortality increased by 14, 14, and 28%, respectively. Convulsive latency was prolonged in some PTZ (100 mg/kg) + L-NAME (40 and 70 mg/kg)-treated groups. In the experimental model and protocol used, it is concluded that (1) the effects of NO are L-NAME- and PTZ-dose dependent; (2) clonic-tonic convulsions are more strongly influenced by NO than limbic, probably because of PTZ limbic structure overstimulation; (3) L-NAME decreases the incidence of CTC and prolongs FLD, GCC, and CTC times to onset, indicating that NO acts as a proconvulsant; and (3) increased GCC, CTC, and mortality that suggests an anticonvulsant effect of NO needs further investigation.
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PMID:Nitric oxide (NO) and convulsions induced by pentylenetetrazol. 1207 82

The aim of this study was to evaluate the role of nitric oxide (NO) upon hyperbaric oxygen (HBO) toxicity in male Sprague-Dawley rats during exposure to 0.5 MPa >99% O(2). In the first experiment, the selective neuronal NO synthase inhibitor 7-nitroindazole (7-NI) was injected intraperitoneally (ip) in 15 rats. Another 15 rats received vehicle injections of peanut oil intraperitoneally. Latency to observable tonic-clonic convulsions and motor activity during the HBO exposure were scored and compared between the control group and the 7-NI group. The results showed that injection of 7-NI (30 mg/kg) significantly prolonged the latency to observable tonic-clonic convulsions. The 7-NI group also showed a significant decrease in motor activity compared with the control group. A second experiment was performed to measure the effect of 7-NI injections upon open-field activity during normobaric conditions. Twenty-four male Sprague-Dawley rats were randomly divided into three groups, each consisting of eight rats receiving 30 mg/kg 7-NI injections, 10 mg/kg 7-NI injections or vehicle injections of peanut oil intraperitoneally, respectively. The results showed that injection of 7-NI led to a significant dose-dependent reduction in horizontal and vertical activities. This study shows that 7-NI prolongs the latency to hyperoxia-induced seizures. However, it also demonstrates that 7-NI in doses ranging from 30 to 10 mg/kg has a secondary effect upon motor behavior in general. It can therefore not be ruled out that the protective effect of 7-NI upon HBO intoxication is partly due to reduced motor activity.
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PMID:Behavioral effects of 7-nitroindazole on hyperbaric oxygen toxicity. 1212

The involvement of nitric oxide (NO) in modulation of seizure susceptibility by delta-opioid agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC80) was examined in mice. Systemic administration of SNC80 (0.1-5 mg/kg, intraperitoneally (i.p.)) decreased the threshold for clonic seizures induced by pentylenetetrazole. The non-specific NO synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (3-20 mg/kg, i.p.), but not the specific inducible NOS inhibitor, aminoguanidine (50 and 100 mg/kg, i.p.) inhibited the proconvulsant effect of SNC80. On the other hand, NO substrate, L-arginine (30 and 60 mg/kg, i.p.) potentiated the proconvulsant effect of a lower dose of SNC80 (0.5 mg/kg). These results support the involvement of NO, produced by constitutive NOS, in the proconvulsant effect of the delta-opioid agonist.
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PMID:The role of nitric oxide in the proconvulsant effect of delta-opioid agonist SNC80 in mice. 1216 20

Electrical stimulation of limbic structures, pharmacological interventions, and getting wet induces wet dog shakes (WDS) in rats. WDS are often associated with the occurrence of seizures. In this study, we evaluated the effects of reduced NO production on physiologically (wetting)- or pharmacologically (kainic acid; KA)-induced WDS and KA-triggered seizures. Following wetting, naive and saline-treated rats displayed more WDS than rats treated with NO synthase (NOS) inhibitor, N omega-nitro-L-arginine (L-NA). In another experiment, WDS and seizures were monitored after KA treatment alone or in combination with L-NA. Again, NOS inhibition reduced the number of KA-triggered WDS but augmented the number and severity of seizures. Our results suggest that not only do physiologically- and kainate-induced WDS share a common mechanism that includes NO, but that there is also an antagonism between WDS and convulsions.
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PMID:Nitric oxide synthase inhibition suppresses wet dog shakes and augments convulsions in rats. 1218 80

The goal of work was to reveal changes in microcirculation of the rat brain and the role of nitric oxide (NO) in development of seizures at hyperbaric oxygen exposure. The Wistar rats with implanted paired platinum electrodes in left and right striatum were used for experiments. The latency of seizures was defined by the EEG, the cerebral blood flow (CBF) was measured by hydrogen clearance. One group of animals was exposed to a 5-ata oxygen, while the others before oxygen treatment were injected with: Nw-nitro-L-arginine methyl ester (L-NAME), blockator of constitutive NO synthase; 7-nitroindozol (7NI), specific inhibitor of neural NO synthase. The latency of seizures was 41 +/- 1.9 min at 5 ata oxygen exposure. CBF was decreased to 10-14% but before seizures it increased to 23 +/- 9%. L-NAME and 7NI prevented development of hyperoxygen hyperemia and onset of seizures. The results indicate occurrence of hyperbaric oxygen changes of the CBF that modulate neurotoxic effects of NO in neurons as well as in cerebral vessels.
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PMID:[Cerebral blood flow modulates hyperbaric oxygen induced neurotoxicity by neuronal and endothelial nitric oxide]. 1223 55


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