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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The single-locus mutant mouse tottering (tg) displays spontaneous seizures that resemble those in human petit-mal epilepsy. In order to examine alterations in GABAA receptor function which could arise as a result of this mutation, the influx of 36Cl- was determined using microsacs (membrane vesicles) isolated from the brain of tg/tg and coisogenic C57BL/6J (+/+) control mice. In microsacs from both tg/tg and +/+ strains, the maximum level of 36Cl- uptake induced by 50 microM GABA was observed during five seconds of incubation at 28 degrees C. Compared to +/+, the GABA-dependent 36Cl- uptake in tg/tg microsacs was significantly lower and faded rapidly during longer incubations. The levels of gated 36Cl- uptake in tg/tg microsacs were 45 +/- 6.3%, 65 +/- 9.9%, and 33 +/- 6.1% of control (+/+) values for 3-, 5-, and 10-s incubations, respectively. GABAA receptor-specific agonists (30 microM), muscimol, isoguvacine and THIP (4,5,6,7-tetrahydroisoazolo-[5,4-c]pyridin-3-ol) induced 36Cl- influx in the order muscimol > GABA > isoguvacine > THIP. This order was similar for both strains, but the agonist-dependent influx was always significantly lower in tg/tg compared to +/+. Treatment of the microsacs with 10 microM H-89, a membrane-permeant inhibitor of the cAMP-dependent protein kinase (protein kinase A, PKA), was without effect on GABA-gated 36Cl- uptake in +/+, but increased the gated uptake in tg/tg microsacs by 44 +/- 16%. PKA was assayed using [gamma-32]ATP and kemptide as the substrate. Triton X-100 (0.1%) increased both the basal and 8-Br-cAMP dependent PKA activity in microsacs by 3-4 four fold, showing that most of the enzyme was intravesicular. In the presence of Triton, the basal activity of PKA in the tg/tg preparations was twice that of +/+, while the strain difference was no longer apparent in assays containing 8-Br-cAMP. The data suggest that an abnormal elevation of protein kinase A activity in tottering mouse brain contributes to an impairment of GABAA receptor function. It is suggested that the resulting loss of inhibition could play a role in induction of the seizures which characterize the mutant phenotype.
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PMID:Reduced function of gamma-aminobutyric acidA receptors in tottering mouse brain: role of cAMP-dependent protein kinase. 856 63

Catabolites of purine nucleotides were measured in the cerebrospinal fluid (CSF) of newborn infants with sepsis, seizures and hydrocephalus using isocratic reversed-phase HPLC. The inosine levels in the CSF of the infants with any of the illnesses were significantly higher when compared with the controls. There was a tendency for hypoxanthine levels to be higher in the group of children with hydrocephalus. No significant differences in the concentrations of xanthine, adenine and uric acid were found. The inosine concentration in the CSF is proposed to be a more sensitive indicator of brain injury than the levels of other CSF purines. The levels of all purine metabolites measured in the CSF showed large individual variations. The ratio between hypoxanthine (as an indicator of ATP breakdown) and uric acid (as a scavenger of oxygen free radicals) concentration is proposed as a new criterion to be used in the evaluation of brain injury.
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PMID:Concentration of purine compounds in the cerebrospinal fluid of infants suffering from sepsis, convulsions and hydrocephalus. 856 8

For further investigation of the epileptogenic properties of pentylenetetrazol (PTZ), membrane currents elicited by PTZ were analysed in native Xenopus oocytes. PTZ elicited a sequence of membrane currents. Two inward currents have been described to be due to a decrease in potassium permeability and an increase in chloride permeability. Experiments performed up to 3 days after preparation of the oocytes showed that PTZ is also able to activate an outward current. This current is: (1) reversed near the potassium equilibrium potential, (2) associated with a decrease in membrane resistance, (3) reduced by tetraethylammonium and caesium, (4) abolished by defolliculation, and (5) blocked by glibenclamide. Thus, the current can be interpreted to be due to an activation of ATP-sensitive potassium (KATP) channels located in the follicle cells. An activation of KATP channels by PTZ may contribute to termination and re-initiation of seizure activity.
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PMID:Activation of ATP-sensitive potassium channels in follicle-enclosed xenopus oocytes by the epileptogenic agent pentylenetetrazol. 859 24

Ketosis is beneficial for seizure control, possibly through induction of cerebral acidosis. However, cerebral intracellular pH has not previously been measured in ketotic humans and the animal data are sparse. We describe a high-fat diet, avidly consumed by rats, that induced consistent and moderate ketosis. Adult male rats were fed either the high-fat ketogenic diet, a high-carbohydrate diet with the same protein content as the ketogenic diet, or regular laboratory chow. Five to 6 weeks later, the rats were anesthetized, paralyzed, and injected with neutral red; their brains were frozen in situ. Intracellular pH of the cerebral cortex and cerebral glucose, lactate, ATP, phosphocreatine, and gama-aminobutyric acid (GABA) levels were measured. Rats fed the ketogenic diet had > 10-fold increase in their plasma ketones, but we noted no significant differences in cerebral pH or in cerebral metabolites and GABA levels among the three groups. Therefore, the antiepileptic effect of the ketogenic diet probably is not mediated by cerebral acidosis or changes in total cerebral GABA levels.
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PMID:Diet-induced ketosis does not cause cerebral acidosis. 859 84

1. Mechanisms that regulate the cerebral circulation have been intensively investigated in recent years. The role of several vasodilator mechanisms has been examined in the cerebral circulation, including nitric oxide (NO), trigeminal peptides and potassium channels, as well as the potent vasoconstrictor endothelin. These mediators appear to play a role in physiological and pathophysiological responses of the cerebral circulation. In the present review, we will focus on some recent developments in each of these areas. 2. Nitric oxide is an important regulator of cerebral vascular tone. Tonic production of NO maintains the cerebral vasculature in a dilated state. NO appears to be an important vasodilator during activation of neurons by excitatory amino acids, somatosensory stimulation and cortical spreading depression. Tonic production of NO appears to be critical in vasodilatation during hypercapnia, although NO may not directly mediate vasodilatation. NO produced by immunological NO-synthase appears to be important in dilatation following exposure to bacterial endotoxin. 3. Calcitonin gene-related peptide (CGRP), released from trigeminal perivascular sensory nerves in the brain, is an extremely potent dilator of brain vessels. CGRP may limit noradrenaline-induced constriction of cerebral vessels and contribute to dilatation during hypotension (autoregulation), reactive hyperaemia, seizures and cortical spreading depression. 4. Activation of potassium channels leads to hyperpolarization of cerebral vascular smooth muscle and appears to be a major mechanism for dilatation of cerebral arteries. Agents that increase the intracellular concentration of cyclic 3' 5'-adenosine monophosphate (cAMP) produce vasodilatation in part by activation of large conductance calcium-activated potassium channels (BKCa) and ATP-sensitive potassium channels (KATP). Activation of both KATP and BKCa channels also appears to contribute to vasodilatation during hypoxia. In contrast to KATP channels, BKCa channels appears to be active under basal conditions, contributing to tonic dilatation of cerebral blood vessels. 5. Endothelin is produced in the brain, but its role in the physiological regulation of cerebral blood flow is not known. Endothelin may contribute to the spasm of cerebral arteries following subarachnoid haemorrhage.
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PMID:Recent insights into the regulation of cerebral circulation. 880 May 65

We assessed the effect of an opener of ATP-sensitive K+ channel, levcromakalim (BRL 38227, (-)6-cyano-3,4-dihydro-2, 2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-1-benzopyran-3-ol) on seizure threshold and severity of the hippocampus-generating partial seizures in rats. For comparison, an ATP-sensitive K+ channel blocker, glibenclamide; K+ channel blocker, tetraethylammonium; Ca2+ channel antagonist, nimodipine and Ca2+ channel agonist, (+/-)-BAY K 8644 (1,4-dihydro-2, 6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridinecarboxyli c acid methyl ester) were also examined. Seizure threshold was determined using pulse number threshold and seizure severity was ascertained using afterdischarge duration. Levcromakalim decreased afterdischarge duration at 10 nmol i.c.v. and decreased pulse number threshold at 100 nmol i.c.v. Tetraethylammonium at 10 nmol i.c.v. increased afterdischarge duration selectively and at 100 nmol i.c.v. induced spontaneous seizures. Glibenclamide (1-100 nmol i.c.v.) failed to change pulse number threshold and afterdischarge duration. Nimodipine (40 mg/kg i.p.) decreased afterdischarge duration and pulse number threshold. BAY K 8644 (1 mg/kg i.p.) decreased pulse number threshold and increased afterdischarge duration. In addition, voltage-clamp recording from neuroblastoma x glioma hybrid cells indicates that levcromakalim inhibited the fast component of Ca(2+)-dependent K+ currents, in addition to the inhibition of T- and L-types of voltage-dependent Ca2+ currents reported (Ito et al., FEBS Lett. 262, 313, 1990). These results suggest that levcromakalim shows anti- and proconvulsive actions in the hippocampus-generating partial seizures in rats and these effects might be, at least partly, caused by inhibiting Ca2+ channel and Ca(2+)-dependent K+ channel, respectively.
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PMID:Anti- and proconvulsive actions of levcromakalim, an opener of ATP-sensitive K+ channel, in the model of hippocampus-generating partial seizures in rats. 888 34

Seizures are the most frequent neurological event in newborns (NBs), provoked often by noxae not apt to cause them in later life. This is because receptor families of excitatory amino acids (EAA) are overexpressed at this stage of brain ontogenesis, which is also why most neonatal seizures rapidly abate, even when neurological deficits persist. The brain's immaturities dictate distinct seizure phenotypes. A classification proposed in the late 1960s has been criticized, and a new one has been advocated, based on correlations between EEGs and behaviors, leading to a classification of seizures into 'epileptic' and 'non-epileptic'. The taxonomic pitfalls of these classifications are discussed, and the notion advanced that many seizures fail to fulfil the criteria to label them as epileptic. While etiological factors have changed in time, the striking dichotomy in outcome has persisted. Many etiologies, often multifactorial, are unique in NBs, and they are discussed with reference to diagnosis and therapies. Four syndromes of NB seizures, accepted into the International Classification of the Epilepsies, are critically analyzed, some appearing to rest on fragile grounds. Controversies persist whether seizures per se are injurious to the immature brain. Clinical studies suggest that neither duration in days or length of seizure phenotypes correlates with outcomes, the most valid prognostic indices being offered by etiologies and by patterns of EEG polygraphy. However, because most seizures are symptomatic, it may be difficult to distinguish morbidity due to underlying pathology from that possibly added by seizures. Animal experiments suggested that they are injurious. The theory of energy failure, postulated to cause a cascade of events leading to inhibitions of DNA, proteins, lipids and disrupted neuronal proliferation, synaptogenesis, myelination, has largely been disproved. Brains of immature animals have been shown to have the oxidative machinery needed to fulfill energy demands, even during status convulsivus. They are also capable of using anaerobic metabolism and require less ATP when aerobic energy production ceases. Recent explanations for the injurious consequences of hypoxic ischemia and of prolonged convulsions postulate that neuronal damage occurs from excessive release of EAA which, by binding to their ligand-gated ionic receptors, cause a large influx of Ca2+, resulting in cell death. Because of the overabundance of EAA receptors in early ontogenesis, the excitotoxic hypothesis would appear attractive, but some observations militate against it. Among these is the dissociation found between the focal neurotoxicities induced by EAA injected into the brain and their absence following the concomitant convulsions. The latter are not blocked by pretreatment with EAA antagonists, while these prevent injuries caused by the injected EAA. There is no convincing evidence that excessive release of EAA occurs during NBs' seizures. Even if it does occur, it has been shown that immature neurons have a better capacity to self-protect from increased Ca2+ influx, and also that direct application of glutamate to immature neurons leads to significantly lower Ca2+ influx. These data raise doubts about the postulated excitotoxicity caused by NBs' seizures, being consistent with the fact that no one, so far, has observed neuronal damage from drug-induced convulsive states in NBs. Lack of overt neuronal injuries does not preclude that long-term subtle changes might be induced by noxae apt to provoke transient ictal events. Thus models developed in our laboratories demonstrate that long-term epileptogenicity results following postnatal O2 deprivation without evidence of neuronal injuries or of long-term behavioral or electrophysiological alteration. However, both age at which hypoxia occurs and specific proconvulsant methods used strictly determine whether increased epileptogenicity will occur.
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PMID:Neonatal seizures: a clinician's overview. 890 38

When ddY mice were pretreated with L-carnitine (5, 10 or 20 mmol/kg), clonic as well as tonic seizures induced by pentylenetetrazol (PTZ) were dose-dependently suppressed. A time/response study (PTZ was injected 1, 5, 15 or 30 min after L-carnitine) showed that the anticonvulsive effects were apparent when the interval between L-carnitine and PTZ administration was 15-30 min. Saline containing 43% sucrose prolonged the latency to the first clonic seizure but was less effective than 20 mmol/kg L-carnitine and did not suppress clonic or tonic seizures. Alterations in brain energy metabolites caused by PTZ including increase of lactate and decrease of ATP and phosphocreatine were also suppressed by L-carnitine. L-carnitine was more potent than D-carnitine in prolonging the latency to the first clonic seizure and in decreasing the frequency of clonic as well as tonic seizures. The anticonvulsive effects of L-carnitine in PTZ-induced seizures may be unrelated to the transport of long-chain acyl CoA since they were not interfered with by D-carnitine.
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PMID:Suppression of pentylenetetrazol-induced seizures by carnitine in mice. 910 73

Brain creatine kinase (CK) catalyzed phosphorus fluxes between phosphocreatine (PCr) and ATP and changes in reactant concentrations were measured using [31P] nuclear magnetic resonance spectroscopy ([31P]NMR) before and during pentylenetetrazole-induced seizures in 7 and 21 day old rats. The CK rate constants measured before seizures were three times higher in the older than in the younger rats. The rate constants increased 60% during seizures in the older rats but did not change or decreased in the younger. Small decreases in PCr were seen during seizures at both ages. A small decrease in ATP was seen at 7 days but not at 21 days.
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PMID:Brain creatine kinase reaction rates and reactant concentrations during seizures in developing rats. 916 86

Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.
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PMID:In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog. 917 48


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