Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.
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PMID:Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions. 890 Oct 1

Most physiologic reflex mechanisms subserve obvious and logical purposes. For example, the arterial baroreflex responds to hypotension by eliciting tachycardia and vasoconstriction, thus increasing cardiac output and raising blood pressure. The raison d'etre for a reflex such as the Bezold-Jarisch is not immediately apparent. Consider, however, the predominant stimulus for the Bezold-Jarisch reflex in the clinical context, namely, rapid forceful ventricular contraction around a relatively empty chamber. Allowing such a situation to continue would be counterproductive. Decreased diastolic filling time, regardless of ventricular contractility, would not permit any improvement in forward cardiac output and hence lead to even further hypotension and thus increasing tachycardia and adrenergic drive to the heart. The cardiac inhibitory reflex acts as a "safety valve," so to speak, slowing the heart rate, increasing diastolic filling, and decreasing afterload. This would be beneficial in myocardial infarction and aortic stenosis. In some persons, however, the reflex may be potentiated, thus predisposing to neurally mediated syncope with relatively minor provocation. We have attempted to explore the role of the cardiac inhibitory reflex in syncope associated with several clinical situations. The advent of direct measurements of sympathetic activity by microneurography, together with the availability of provocative testing such as upright tilt and programmed electrical cardiac stimulation, has provided much new insight but has also given rise to a host of additional questions. Mechanisms other than the Bezold-Jarisch reflex may be implicated. Induction of vasodepressor syncope in heart transplant recipients, as well as the association of bradycardia and syncope with partial seizures, provides some evidence that left ventricular mechanoreceptors may not be the exclusive afferent trigger for syncope and that central mechanisms may be implicated. The study of biochemical mediators such as nitric oxide and serotonin, acting perhaps at a central level, holds promise for an increased understanding of basic cardiovascular physiology, as well as for effective therapy for neurally mediated syncope. These biochemical mediators may in and of themselves give rise to neurogenic syncope or may act to increase the gain of the cardiac inhibitory reflex at a central level.
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PMID:Neurocardiogenic syncope. 890 95

The effects of nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA) on seizures induced by excitatory amino acids, bicuculline, pentylenetetrazol and pilocarpine were studied in mice. NNA (10 and 40 mg kg-1, i.p.) enhanced the susceptibility to intracerebroventricular (i.c.v.) kainate (KA) which was reflected by a decrease in its convulsant dose 50% (CD50) from 0.66 nmol to 0.38 and 0.29 nmol/mouse, respectively. Also, NNA (40 mg kg-1) increased the KA-induced mortality. Conversely, NNA (40 mg kg-1) produced an anticonvulsant effect against i.c.v. glutamate whose CD50 value was significantly elevated from 0.49 mumol to 0.84 mumol/mouse. The convulsive activity of i.c.v. N-methyl-D-aspartic acid (NDMA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) was not affected by the pretreatment with NNA (40 mg kg-1). NNA (5-40 mg kg-1) also potentiated the convulsive action of systematic KA and KA-induced mortality but (up to 40 mg kg-1) remained without effect on seizures produced by bicuculline, N-methyl-D, L-aspartic acid (NMDLA), pentylenetetrazol, and pilocarpine. Only bicuculline-produced lethality was significantly enhanced. It may be concluded that the manipulation of the NO level affects differently seizures arising from a diffuse stimulation of glutamate receptors and seizures resulting from an activation of an individual subtype of these receptors. It is noteworthy that in the majority of convulsive tests used in this study, NNA exerted no modulatory effect.
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PMID:NG-nitro-L-arginine differentially affects glutamate- or kainate-induced seizures. 890 65

The effect of the nitric oxide synthase (NOS) inhibitors N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) on seizures induced by N-methyl-D-aspartate (NMDA), pilocarpine (PIL) and pentylenetetrazol (PTZ), as well as on the electroconvulsive threshold was studied in mice. It was found that L-NAME and 7-NI decreased the dose of NMDA necessary to produce clonic convulsions in 50% of animals (CD50). Such a proconvulsant effect was not observed in mice pretreated with N-nitro-D-arginine methyl ester (D-NAME), an inactive isomer of L-NAME. Neither L-NAME nor 7-NI affected the convulsions induced by PIL (clonic seizures) or PTZ (clonic and tonic seizures), having no effect on their CD50 values. Similarly, neither NOS inhibitor affected the electroshock threshold. These results, together with some literature data, indicate that nitric oxide (NO) may be regarded as an anticonvulsant substance in relation to seizures induced by NMDA and other excitatory amino acids, but not by other agents, in mice.
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PMID:The role of nitric oxide in chemically- and electrically-induced seizures in mice. 891 93

In a previous study, we reported that the sustained increase in CBF concomitant with seizures induced by kainate is mainly due to the potent vasodilator nitric oxide (NO). However, the production site of NO acting at cerebral vessels was undetermined. In the present study, we investigated whether NO responsible for the cerebral vasodilation is of either neuronal or endothelial origin. We used a putative selective inhibitor of neuronal NO synthase, 7-nitro indazole (7-NI). CBF was measured continuously in parietal cortex by means of laser Doppler flowmetry in awake rats. Systemic variables and electroencephalograms were monitored. Kainate (10 mg/kg i.p.) was given to rats previously treated with saline (n = 8) or 7-NI (25 mg/kg i.p., n = 8) or L-arginine (300 mg/kg i.p., n = 8) followed 30 min later by 7-NI (25 mg/kg i.p.). Under basal conditions, 7-NI decreased CBF by 27% without modifying the mean arterial blood pressure. Under kainate, 7-NI prevented significant increases in CBF throughout the seizures despite sustained paroxysmal electrical activity. L-arginine, the substrate in the production of NO, prevented any decrease in CBF under 7-NI in basal conditions and partially, but nonsignificantly, reversed the cerebrovascular influence of 7-NI during seizures. In a separate group of rats (n = 6), inhibition of cortical NO synthase activity by 7-NI was assayed at 73%. The present results show that neurons are the source of NO responsible for the cerebrovascular response to seizure activity after kainate systemic injection.
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PMID:Nitric oxide of neuronal origin is involved in cerebral blood flow increase during seizures induced by kainate. 897 91

THE response of hippocampal CA3 neurones to commissural stimulation, as expressed by the orthodromic population spike (PS2) recorded in anaesthetized rats, was increased when the recording micropipette contained the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (20 mM). The increase was stable upon repeated stimulation. When the recording micropipette contained the NO donor sodium nitroprusside (SNP; 10 mM) the amplitude of PS2 elicited by low and middle stimulus strength (Istim) rapidly decreased, while remaining unchanged at higher Istim. When the SNP-containing microelectrode was maintained in place for longer, the depression of PS2 observed at low and medium Istim disappeared and PS2 increased at high Istim. This long-term SNP-induced increase in PS2 at high Istim was reduced by pretreatment with cycloheximide (5 mg kg-1, i.p.). These data, which provide the first demonstration that in situ manipulation of NO produces dual effects on neuronal responsiveness in a highly seizure-prone brain region, suggest that tonic levels of endogenous NO reduce the excitability of CA3 pyramidal neurones, whereas long-term overexposure to NO causes hyperexcitability possibly via genomic mechanisms.
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PMID:Effects of in situ manipulation of nitric oxide on rat hippocampal CA3 neurone excitability. 898 58

Nitric oxide may be involved in seizure phenomena even though data often seem to be contradictory. This prompted us to study the influence of nitric oxide upon electrically and chemically induced seizures. The effects of nitric oxide synthase inhibitor, NG-nitro-L-arginine (NNA), on pentylenetetrazol-, aminooxyacetic acid-, aminophylline-induced seizures or electroconvulsive shock were evaluated. NNA was applied at 1, 10 and 40 mg/ kg 0.5 and 2.0 h before chemical seizures and at 1 and 40 mg/kg 0.5 and 2.0 h prior to electroconvulsions. The nitric oxide synthase inhibitor (up to 40 mg/ kg) did not affect the susceptibility of mice to pentylenetetrazol, amino-oxyacetic acid or electroconvulsions. However, NNA significantly enhanced the convulsive properties of aminophylline when applied at 40 mg/kg, 0.5 h before the test. The CD50 value for aminophylline-induced clonus and tonus/ mortality was decreased from 233 to 191 and from 242 to 212 mg/kg, respectively. However, this pretreatment also led to a significant increase in the plasma levels of theophylline. Our results suggest that differential effects of NNA on chemically-induced convulsions might in some cases be associated with a pharmacokinetic interaction.
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PMID:NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice. 901 1

Long-term potentiation (LTP), a model of activity-dependent synaptic plasticity and of certain forms of memory, comprises the persistent enhancement of excitatory neurotransmission that results from high-frequency activation. A presynaptic component of LTP is thought to be modulated by a retrograde messenger generated by the postsynaptic neuron. Arachidonic acid, nitric oxide, carbon monoxide and PAF have each been proposed as retrograde messengers in LTP, but arachidonic acid, unlike PAF, requires NMDA receptor activation. A PAF antagonist (BN 52021) that provides neuroprotection in ischemia-reperfusion displaces [3H] PAF bound to presynaptic membranes, blocks PAF-induced glutamate exocytosis and inhibits LTP. An antagonist selective for the intracellular PAF binding site (BN 50730) did not affect LTP, nor did BN 52021 modify NMDA currents. LTP was induced with weak synaptic stimulation coupled with postsynaptically administered enzyme resistant mcPAF. Theta-burst stimulation (10 min) after bath applications of mcPAF (1 microM) induced APV-independent LTP that was blocked by 5 microM BN 52021. When this antagonist was infused into the hippocampus before or immediately after training, it impaired memory of inhibitory avoidance training in the rat. Memory was not altered if the antagonist is infused 30 or 60 min after training. Moreover, mcPAF enhances memory on retention test performance of step-down inhibitory avoidance habituation and learning in rats. Also, memory was studied using a caudate nucleus-dependent cued water maze task. Rats received an 8 trial (30 s intertrial interval) training session in which a visible cued escape platform was located in a different quadrant of the maze of each trial. Following trial 8, the rats received a unilateral post-training intra-caudate injection of mcPAF (1 microgram/0.5 microliter), BN 52021 (0.5 microgram/0.5 microliter) or vehicle. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. The retention test escape latencies of rats given mcPAF were significantly lower than those of the vehicle-injected controls, indicating a memory enhancing effect of mcPAF. Injection of mcPAF did not affect retention when administered 2 h post-training, indicating a time-dependent effect of mcPAF on memory. The latencies for animals injected with BN 52021 were significantly higher than those of the controls, indicating that antagonism of endogenous PAF impairs memory. The findings show that PAF plays a role in memory formation in a caudate-mediated cued discrimination task. Administration of BN 52021 2 h post-training had no affect on retention, indicating a time-dependent effect of endogenous PAF on memory formation. PAF, the most potent bioactive lipid known, modulates excitatory synaptic transmission, neuronal plasticity and memory. When PAF production is overstimulated as in seizures or ischemia, it becomes neurotoxic.
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PMID:Bioactive lipids in excitatory neurotransmission and neuronal plasticity. 901 70

The deep rostral piriform cortex contains a site (area tempestas) in which focal application of picomole amounts of bicuculline, a GABA antagonist, triggers limbic motor seizures which are dependent upon activation of both N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyloxole-4-proprionate subtypes of glutamate receptors. In the present study we determined whether nitric oxide can influence the local modulation of seizure initiation by bicuculline. Nitric oxide and the nitric oxide precursor L-arginine, alone or in combination with low doses of bicuculline were focally administered into the area tempestas of rats. While nitric oxide alone had no significant convulsant effect, L-arginine alone (30-240 nmol) induced brief myoclonic episodes. Nitric oxide (0.7 nmol) and L-arginine (30 nmol) markedly potentiated the seizures evoked by a low dose of bicuculline. The effect of L-arginine was prevented by focal pretreatment with an inhibitor of nitric oxide synthesis, N-nitro-L-arginine methyl ester. However, N-nitro-L-arginine methyl ester did not attenuate the convulsant effect of bicuculline or kainate alone when focally administered into area tempestas. The data demonstrate that exogenously applied nitric oxide or its precursors can enhance seizure triggering activity. However, the data also indicate that L-arginine-nitric oxide pathway does not normally contribute to seizure expression from area tempestas, as N-nitro-L-arginine methyl ester alone did not attenuate focally-evoked seizures.
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PMID:The role of nitric oxide in focally-evoked limbic seizures. 902 81

Nitric oxide (NO) formation has been shown in many neuronal tissues subserves a variety of functions. N-Methyl-D-aspartate (NMDA) receptor stimulation which releases nitric oxide and raises cGMP levels, mediates epileptiform activity induced by various agents. Disinhibition of inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and/or activation of NMDA receptor appears to be factors involved in the initiation and generalization of the pentylenetetrazole (PTZ) induced seizures. In the present study, we examined the effects of N(omega)-nitro-L-arginine methylester (L-NAME) which inhibits nitric oxide synthase, on PTZ and strychnine induced seizures in mice. L-NAME (100 mg/kg) significantly prolonged the onset time of tonic generalized extension without affecting myoclonic jerks and tonic-clonic convulsions. L-NAME (200 mg/kg) significantly delayed three characteristic behavioral changes including first myoclonic jerk (FMJ), generalized clonic seizure (GCS) and tonic generalized extension (TGE). The effects of L-NAME were reversed by L-arginine (1000 mg/kg). L-NAME (100 and 200 mg/kg) significantly delayed the onset time of strychnine induced TGE. The effects of both doses of L-NAME were reversed by L-arginine. In conclusion, our results demonstrate that NO synthase inhibition suppresses the onset time of PTZ and strychnine induced seizures. Under the light of our current knowledge NO synthase inhibitors seem far away to be considered as a group of antiepileptic drugs. On the other hand there are some strong evidences about the role of NO in central pathophysiological mechanisms.
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PMID:L-NAME inhibits pentylenetetrazole and strychnine-induced seizures in mice. 912 36


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