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)

Bilateral electrolytic lesions into the red nucleus (RN) of rat elicit an increase in susceptibility to seizures induced by pilocarpine, kainic acid, isoniazid, pentylenetetrazole, bicuculline and maximal electric shock (MES). It was also observed that carbachol-induced wet-dog shakes were increased in the RN-lesioned rats. The brain acetylcholine (ACh) and gamma-aminobutyric acid (GABA) concentrations were significantly decreased in the striatum and substantia nigra, respectively. There were no changes in electroencephalogram (EEG) recordings in the RN-lesioned group compared with sham-operated rats. Based on the results it is proposed that the RN is involved in the generalization and acceleration of seizure activity through the cholinergic and GABA-ergic system.
 ...
PMID:Susceptibility to seizures produced by chemical convulsants and maximal electric shock in rats after electrolytic lesions into the red nucleus. 153 84

We endeavored to determine whether three behavioral effects of melatonin in rodents, i.e., depression of locomotor activity in hamsters, analgesia in mice, and impairment of 3-mercaptopropionic acid (3-MP) convulsions, exhibited the time dependency known to occur for several neuroendocrine effects of the hormone. Activity was monitored and registered by means of an optical actometer, and analgesia was assessed by the hot-plate procedure. Locomotor activity, analgesia, and seizure susceptibility were maximal at the beginning of the scotophase and minimal at noon. The effects of melatonin on the three parameters peaked at early night. The administration of the benzodiazepine antagonist flumazenil, although unable by itself to modify locomotor activity, pain, or seizure threshold, blunted the activity of melatonin. These results suggest that the time-dependent effects of melatonin on specific rodent behaviors may be mediated by central synapses employing gamma-aminobutyric acid (GABA) as an inhibitory transmitter.
 ...
PMID:Chronopharmacology of melatonin: inhibition by benzodiazepine antagonism. 156 63

In vivo experiments were carried out to examine whether the period during which gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus matures is associated with a decrease in epileptogenesis. Seizures were elicited with bipolar electrodes stereotactically positioned in the hippocampus of urethane-anesthetized rat pups from postnatal (PN) 7 through 28 days of age. No clinical seizure activity was detected but electrographic seizures (afterdischarges) were induced at all ages. Afterdischarge thresholds (ADT) varied inversely with age. However, the durations of initial afterdischarges and the degree of lengthening of afterdischarges with the rapidly recurring hippocampal seizure (RRHS) protocol were not different for the various age animals studied. Paired pulse inhibition was assessed with a twin pulse paradigm that has been shown to monitor GABAergic inhibition. Measurements were made before and 60 min after a single seizure and again 60 min after the RRHS protocol. At no age was there a significant change in paired pulse inhibition after a single seizure. After RRHS there was a significant reduction of paired pulse inhibition only in the groups that had manifested adult levels of paired pulse inhibition in pre-seizure measurements (greater than or equal to PN 21). These studies indicate that heightened epileptogenesis in the young hippocampus cannot simply be explained on the basis of an immaturity of GABA-mediated inhibition.
 ...
PMID:Ontogeny of epileptogenesis in the rat hippocampus: a study of the influence of GABAergic inhibition. 160 89

The anticonvulsant, adverse and biochemical effects of the novel antiepileptic drug vigabatrin (gamma-vinyl GABA), which increases GABA (gamma-aminobutyric acid) levels by inhibition of the GABA degrading enzyme GABA aminotransferase, were examined in amygdala-kindled rats after acute and chronic administration. Vigabatrin proved to be a potent anticonvulsant drug at acute doses (100-200 mg/kg), but during chronic administration, the anticonvulsant activity of the treatment was lost already in the second week of treatment. Tolerance also developed to the adverse effects, i.e. hypothermia, sedation and motor impairment. Determination of vigabatrin in plasma indicated that tolerance was not due to declining drug levels. Furthermore, determination of endogenous amino acids in plasma showed that GABA levels were highly elevated throughout the period of treatment, although the extent of GABA accumulation decreased in the second week. After cessation of chronic treatment with vigabatrin, there was no clear indication of withdrawal symptoms, except a prolonged seizure or afterdischarge duration in experiments with 100 mg/kg per day. The data suggest that chronic treatment with vigabatrin may be associated with a loss of anticonvulsant efficacy, at least when the drug is given as monotherapy.
 ...
PMID:Development of tolerance to the anticonvulsant effect of vigabatrin in amygdala-kindled rats. 161 78

Chronic exposure to ethanol is associated with the development of tolerance to the acute effects of ethanol and a withdrawal syndrome characterized by anxiety and seizure susceptibility. In the present study we examined the ability of flumazenil (Ro15-1788), a benzodiazepine receptor antagonist, to reverse neuronal and behavioral manifestations of ethanol tolerance and dependence. A single injection of flumazenil (10 mg/kg, 14 hr before withdrawal) to mice administered a liquid diet containing ethanol for 10 days, reduced seizure severity during withdrawal from ethanol. Acute tolerance to ethanol-induced hypothermia was not sensitive to flumazenil treatment, but tolerance and diazepam-induced cross-tolerance to the ataxic effects of ethanol were reversed by a single injection of flumazenil given 2 to 26 hr before evaluation of tolerance. At a biochemical level, the ability of benzodiazepine inverse agonists (e.g., Ro15-4513) to reduce the activity of gamma-aminobutyric acid (GABA) receptor-operated chloride channels may represent a neuronal manifestation of ethanol dependence (Buck and Harris, 1990). Flumazenil treatment of ethanol-dependent mice 14 hr before isolation of brain membrane vesicles partially reversed the augmentation of Ro15-4513 inhibition of muscimol-stimulated 36Cl- uptake in vitro. These results demonstrate that brief occupation of benzodiazepine receptors by an antagonist may reset the cellular mechanisms responsible for the development of ethanol tolerance and dependence, and support the hypothesis that increased sensitivity to benzodiazepine inverse agonists is involved in the development of ethanol dependence.
 ...
PMID:Reversal of alcohol dependence and tolerance by a single administration of flumazenil. 164 33

Treatment with benzodiazepine agonists is associated with the development of behavioral tolerance and receptor downregulation, whereas antagonist administration has been reported to lead to increased activity and receptor upregulation. To determine the effects of chronic inverse agonist administration, mice were treated with FG-7142 (20 mg/kg/day) by implanted s.c. osmotic pumps for 1 to 14 days. No seizures were observed in FG-7142-exposed animals. Open-field activity was unchanged as compared to controls at days 1 and 2, but was elevated significantly at days 4 and 7. Activity was reduced below control values at day 14. Benzodiazepine receptor binding determined in vivo was unchanged for days 1, 4 and 7 within the hippocampus but was elevated at day 14. Binding remained unchanged in the cortex, cerebellum, hypothalamus and pons-medulla for the duration of drug exposure. Cortical benzodiazepine binding assessed in vitro was unchanged at days 1 and 2 but increased at days 4, 7 and 14 vs. vehicle treated controls. Binding at the gamma-aminobutyric acid site was increased at day 7 whereas binding of t-[35S]butylbicyclophosphoro-thionate was increased at days 7 and 14 of FG-7142 exposure. Maximal muscimol-slimulated [36Cl-] uptake was elevated at days 4, 7 and 14 compared to day 1 of exposure. These results demonstrate that chronic continuous exposure to FG-7142 is associated with an absence of kindled seizures and with behavioral and neurochemical changes indicative of gamma-aminobutyric acidA receptor upregulation.
 ...
PMID:Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142. 164 96

The effect of intranigral application of a gamma-aminobutyric acid (GABA) synthesis inhibitor, was examined in 3 different rat seizure models. Bilateral intranigral infusion of isoniazid (150 micrograms) did not potentiate the effect of subcutaneous administration of a threshold dose (1.5 mg/kg) of the GABA antagonist bicuculline. Similarly, following pretreatment with intranigral isoniazid, neither severity nor latency to onset of seizures elicited by systemic injection of kainic acid (9 mg/kg) were modified. In addition, convulsive seizures evoked by the focal injection of bicuculline methiodide (40 ng) in an epileptogenic site within the deep prepiriform cortex (area tempestas) were not potentiated by intranigral isoniazid. These results were in sharp contrast to the marked potentiating effect of intranigral isoniazid (150 or 85 micrograms) on seizures induced by systemic administration of a subconvulsant dose of pilocarpine (150 mg/kg). In addition, we attempted to evoke a proconvulsant action from striatum. The striatum, origin of GABAergic projections to substantia nigra, is a region in which application of GABA antagonists have been found to be anticonvulsant in several seizure models. We therefore examined the effect of bilateral intrastriatal infusion of the GABA agonist, muscimol (5 ng) on the convulsant effect of threshold doses of systemically administered bicuculline (1.5 mg/kg). As was true with intranigral isoniazid, no proconvulsant effect was found using intrastriatal muscimol. Our data demonstrate that whereas striatonigral GABA circuitry can be activated by exogenous treatments so as to produce anticonvulsant actions in most seizure models, suppression of this circuitry does not potentiate convulsant activity in many of the same models.
 ...
PMID:Lack of proconvulsant action of GABA depletion in substantia nigra in several seizure models. 165 Feb 83

Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.
 ...
PMID:Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy. 165 57

Benzodiazepines are psychoactive substances classically used for their anticonvulsant properties in neonates as well as in adults. In a previous work, we have shown that seizures lead to an age-dependent upregulation of central benzodiazepine binding sites measured in isolated rat cerebral membranes. However, information concerning regional changes in the receptor density was lacking. In our present study, the effects of bicuculline-induced seizures were investigated by quantitative autoradiography of central benzodiazepine receptors in developing rats and in adults. Animals were killed 30 min after an intraperitoneal injection of either saline or a convulsive dose of bicuculline. Benzodiazepine binding sites in brain sections were labeled by [3H]flunitrazepam. Generalized seizures induced a widespread increase in benzodiazepine receptors, with a marked enhancement in structures that mediate seizure activity, such as substantia nigra, amygdala, septum, and hippocampus. The addition of exogenous gamma-aminobutyric acid to the incubation medium increased benzodiazepine binding by the same order of magnitude whether rats were given saline or bicuculline, suggesting that additional benzodiazepine sites are also functionally linked to gamma-aminobutyric acid receptors. The age-related postictal increase in benzodiazepine receptors might reflect a compensatory response for protection against recurrent seizures, especially in newborns.
 ...
PMID:Autoradiographic changes in central benzodiazepine binding sites and their coupling to gamma-aminobutyric acid receptors after seizures in the developing rat. 165 33

Experiments examining seizure sensitivity were conducted on adult male offspring exposed to diazepam at 1.0 or 2.5 mg/kg per day in utero over gestational days 14-20. Threshold dosages to facial clonus, myoclonic jerk, clonic seizure, and extensor tonus were determined via i.v. infusion of bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), picrotoxin, pentylenetetrazol, caffeine and strychnine. Relative to uninjected and vehicle-exposed adult male offspring, prenatal diazepam administration reduced the threshold for bicuculline- and DMCM-induced facial clonus and myoclonic jerk by 40-50%. The threshold dosages to facial clonus, myoclonic jerk and clonic seizure from picrotoxin infusion were similarly reduced in animals exposed to diazepam in utero. In contrast, seizure thresholds to pentylenetetrazol, caffeine and strychnine were not affected by early developmental exposure to diazepam. In parallel biochemical studies, an increased sensitivity to the antagonistic effects of bicuculline methiodide on gamma-aminobutyrate (GABA)-stimulated chloride influx was observed in cortical synaptoneurosomes from adult male progeny of diazepam-treated dams. The results are interpreted to reflect a long-lasting alteration in the function of the GABA/benzodiazepine receptor complex by prenatal diazepam exposure that is manifest at the behavioral and neurochemical level in a pharmacologic specific manner.
 ...
PMID:Gestational exposure to diazepam increases sensitivity to convulsants that act at the GABA/benzodiazepine receptor complex. 165 53


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