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

In response to NMDA receptor activation, hippocampal, striatal and cerebellar neurons synthesize nitric oxide (NO), which in turn elevates cGMP levels via guanylate cyclase. NO is increasingly being considered as a transsynaptic retrograde messenger, involved in neuronal plasticity. The effect of an inhibitor of NO synthase, L-NG-nitroarginine (NOArg), was studied on amygdala kindling and on kindled seizures in rats. NOArg increased kindling rate, particularly in its initial period, but did not modify seizure severity in previously kindled rats, although we have no definitive explanation for this effect. However, an enhanced post-synaptic excitability could be attributed to the blockade of the negative feed-back exerted by NO on the NMDA receptor.
 ...
PMID:A nitric oxide (NO) synthase inhibitor accelerates amygdala kindling. 138 71

High amplitude spiking representative of seizures, accompanied by an unusual motor behavior pattern of rearing and forelimbic clonus resembling "boxing," was elicited by microinjection of the cholinergic agonist, carbachol, 4 micrograms, into the medial prefrontal cortex of the rat. A rating scale devised to score the behavior revealed a motor pattern elicited by carbachol from the medial anterior cortex which was similar to that described by Racine for electrical stimulation of the amygdala. Topographical analysis of the areas surrounding the medial anterior cortex region revealed that the motor manifestations of seizures were elicited over a wide region of the anterior cortex, with scores significantly lower at carbachol microinjection sites greater than 1 mm rostral, 2 and 3 mm caudal, and 2 mm lateral to the standard medial prefrontal cortex site. Unilateral microinjection of carbachol yielded motor seizures primarily from the contralateral forepaw, suggesting involvement of a crossed pathway. Retrograde tracing with fast blue dye, combined with immunostaining for choline acetyltransferase and NADPH-diaphorase, found that the cholinergic neurons innervating the standard microinjection site were the dorsolateral tegmental cells, as previously reported, which have been shown to also contain substance P and corticotropin releasing factor. In addition, cholinergic neurons of the nucleus basalis of Meynert region were found to innervate the standard microinjection site. These findings implicate cholinergic innervation of the rostral cortex in classical limbic seizures.
 ...
PMID:Anatomical analysis of frontal cortex sites at which carbachol induces motor seizures in the rat. 317 34

Stargazer mutant mice inherit a recessive neuronal excitability phenotype featuring frequent non-convulsive spike-wave seizures that arise from synchronous bursting in neocortical, thalamic and hippocampal networks. Immunocytochemistry reveals that granule cells in the mutant dentate gyrus aberrantly express neuropeptide Y (NPY) at multiple ages following the developmental onset of seizures. The ectopic NPY is selectively concentrated in the mossy fibers, co-localizing with the releasable dense core vesicle pool. The NPY content of native NPY+local circuit neurons is also elevated in the mutant CNS. There is no concurrent elevation of hippocampal 72 kDa heat shock protein (HSP72), glial fibrillary acidic protein (GFAP) or NADPH-diaphorase, three markers that are induced during cellular injury, and no evidence of granule cell loss. Since mossy fiber NPY expression appears after the developmental onset of spike-wave discharges and can be induced in wild type granule cells by electrical stimulation, the altered peptide phenotype is likely to reflect transynaptic gene induction triggered by synchronous bursting. These results link a specific pattern of repetitive synaptic input with selective molecular plasticity in dentate granule cells that may contribute to dynamic modifications in hippocampal network excitability.
 ...
PMID:Aberrant expression of neuropeptide Y in hippocampal mossy fibers in the absence of local cell injury following the onset of spike-wave synchronization. 747 19

The effect of L-arginine (L-Arg), D-arginine (D-Arg), N-nitro-L-arginine methyl ester (L-NAME) and N-monomethyl-L-arginine (L-NMMA) on the kainate-induced seizures was studied in mice. It was found that the precursor of nitric oxide (NO) L-Arg (150-600 mg/kg i.p.) increased dose-dependently the dose of kinate necessary to produce clonic convulsions in 50% of the animals (CD50). Such an anticonvulsant effect was not observed in mice pretreated with D-Arg (150-600 mg/kg i.p.), the latter drug not being a substrate for NO formation. The inhibitors of NO synthase L-NAME and L-NMMA, both administered in doses of 30-30 mg/kg i.p., reduced the convulsive threshold by decreasing the CD50 of kainate. Moreover, L-NAME (3 mg/kg) antagonized the anticonvulsant effect of L-Arg (300 mg/kg). These results indicate that NO may play a role of an endogenous anticonvulsant substance in mice.
 ...
PMID:The role of nitric oxide in the kainate-induced seizures in mice. 751 94

In paraformaldehyde-fixed sections of healthy brain, glial cells at the light-microscope level do not contain measurable levels of NADPH-diaphorase. However, after a variety of lesions in the mouse brain, some reactive astrocytes express varying amounts of this enzyme. Following stab wounds, activated astrocytes or related glial cells surrounding the lesion, contained moderate to high levels of NADPH-diaphorase in the cerebellum, midbrain, thalamus, striatum, hippocampal formation and neocortex. Double-labelling experiments confirmed that this corresponds to an inducible form of nitric oxide synthase, similar to that found in activated macrophages. Within the lesion there were large numbers of macrophages which also contained NADPH-diaphorase. After 10 min of global hypoxic ischaemia, some reactive astrocytes also contained NADPH-diaphorase. These cells were confined to the dorsal part of the hippocampal formation (the dentate fascia and CA1 areas) and to the anterolateral striatum. More focal ischaemic damage, produced by dividing an arterial branch, also produced a rim of reactive astrocytes containing NADPH-diaphorase, that surrounded the area of necrosis. Low levels of NADPH-diaphorase were induced within one day of a stab wound and the enzyme activity reached near maximal levels by two days postlesion. Moderate NADPH-diaphorase activity was still present at 63 days postlesion, but only a small number of astrocytes were stained in the immediate vicinity of the lesion. These experiments confirm that NADPH-diaphorase activity represents inducible nitric oxide synthase in activated astrocytes and probably in inflammatory macrophages. We conclude that a high proportion of activated astrocytes and a small proportion of invading macrophages are induced to express moderate to high levels of nitric oxide synthase following neuronal damage. Our results indicate that following a variety of lesions reactive astrocytes are synthesizing significant levels of nitric oxide within 24 h. This nitric oxide may be involved in modulating the likelihood of epileptic seizures.
 ...
PMID:NADPH-diaphorase activity in activated astrocytes represents inducible nitric oxide synthase. 752 Jan 36

The nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (NNA) and the putative brain-selective NO synthase inhibitor 7-nitroindazole (7-NI) were used to determine the role of endogenous NO on seizures induced by kainic acid (KA) in rats and KA, pilocarpine, bicuculline, picrotoxin and pentylenetetrazole (PTZ) in mice. Rats given a subconvulsant dose of KA (6 mg/kg, i.p.) had seizures after they had been pretreated with NNA (50 mg/kg, i.p.). With a higher dose of KA (12 mg/kg, i.p.), NNA caused an increase in wild running seizures and mortality. Unlike NNA, 7-NI had no effect on KA-induced seizures. Similarly, NNA but not 7-NI caused a worsening of seizures in mice measured as a shortening of seizure latency and an increase in wild running and mortality. The effect of NNA on seizure latency was completely reversed by the competitive substrate for NO synthase, L-arginine. NNA had no effect on seizure latency following any of the other convulsants and increased mortality following pilocarpine and picrotoxin alone. Our results indicate that NNA may enhance the severity of KA-induced seizures through suppression of NO synthase activity in the vascular endothelium. The resulting impairment of cerebrovascular autoregulation may cause a mismatch between metabolic demand and blood flow during seizures leading to facilitation of spread. The absence of a comparable effect of NNA on other seizure models may indicate differences in the degree to which seizure activity in different models is influenced by the metabolic impairment secondary to decreased blood flow.
 ...
PMID:Inhibition of NO synthase increases the severity of kainic acid-induced seizures in rodents. 752 58

Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using the intracarotid 133Xe clearance method or laser-Doppler flowmetry. EEG activity was recorded. Chronic treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthase (NOS) inhibitor (400 mg/kg total), suppressed brain NOS by > 97% and prolonged seizure duration from 6 +/- 1 (saline-treated controls) to 12 +/- 2 min. In the L-NA-treated group, the CBF increase was sustained as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inactive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS activity, ranging from 87 to 100%. The duration of seizures in this group (average 8 +/- 2 min) corresponded directly to the magnitude of reduction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA results indicated that NOS inhibition had to exceed 95% before any effect on seizure duration could be seen.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats. 753 May 79

L-Arginine-derived nitrogen monoxide (NO) formation was determined in different regions of the rat brain during kainate-induced seizures. NO was trapped in vivo as a paramagnetic mononitrosyl-iron diethyldithiocarbamate complex, the concentration of which was determined ex vivo by cryogenic electron spin resonance spectroscopy. Basal NO formation (0.3-0.8 nmol g-1 tissue 30 min-1) was detected in the brain of control rats. In kainate-injected rats NO formation was increased six-fold within 30-60 min in the amygdala/temporal cortex region, and up to 12-fold, though more slowly, in the remaining cortex. The kainate-elicited convulsions and NO formation were attenuated in animals pretreated with either 7-nitroindazole, a specific inhibitor of neuronal NO synthase, or diazepam. These findings identify NO as a proconvulsant mediator in kainate-evoked seizures.
 ...
PMID:Nitric oxide promotes seizure activity in kainate-treated rats. 753 56

The role of nitric oxide (NO) in the increase in local cerebral blood flow (LCBF) elicited by focal cortical epileptic seizures was investigated in anesthetized adult rats. Seizures were induced by topical bicuculline methiodide applied through two cranial windows drilled over homotopic sites of the frontal cortex, and LCBF was measured by quantitative autoradiography by using 4-iodo[N-methyl-14C]antipyrine. Superfusion of an inhibitor of NO synthase, N omega-nitro-L-arginine (NA; 1 mM), for 45 min abolished the increase of LCBF induced by topical bicuculline methiodide (10 mM) [164 +/- 18 ml/100 g per min in the artificial cerebrospinal fluid (aCSF)-superfused side and 104 +/- 12 ml/100 g per ml in the NA-superfused side; P < 0.005]. This effect was reversed by coapplication of an excess of L-arginine substrate (10 mM) (218 +/- 22 ml/100 g per min in the aCSF-superfused side and 183 +/- 31 ml/100 g per min in the NA + L-Arg-superfused side) but not by 10 mM D-arginine, a stereoisomer with poor affinity for NO synthase (193 +/- 17 ml/100 g per min in the aCSF-superfused side and 139 +/- 21 ml/100 g per min in the NA + D-Arg-superfused side; P < 0.005). Superfusion of the guanylyl cyclase inhibitor methylene blue attenuated the LCBF increase elicited by topical bicuculline methiodide by 25% +/- 16% (P < 0.05). The present findings suggest that NO is the mediator of the vasodilation in response to focal epileptic seizures.
 ...
PMID:Nitric oxide mediates the increase in local cerebral blood flow during focal seizures. 753 26

In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats. 753 78


1 2 3 4 5 6 7 8 9 10 Next >>