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

A number of animal models of generalized absence seizures in rodents are described. These include absence seizures induced by gamma-hydroxybutyrate (GHB), low dose pentylenetetrazole, penicillin, THIP, and AY-9944. All of these models share behavioral and EEG similarity to human absence seizures and show pharmacologic specificity for antiabsence drugs such as ethosuximide and trimethadione. Moreover, the absence seizures induced by these agents are exacerbated by GABAergic agonists, a property unique to experimental absence seizures. These models are predictable, reproducible, and easy to standardize. They are useful both in studying mechanisms of pathogenesis of absence seizures as well as in screening for antiabsence activity of potential antiepileptic drugs.
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PMID:Pharmacological models of generalized absence seizures in rodents. 138 Sep 80

Neonatal Long-Evans hooded rats were treated with AY-9944, a cholesterol biosynthesis inhibitor, every 6 days for 7 weeks to induce a permanent absence-like epileptic condition. AY-9944-treated rats averaged 50 +/- 15 generalized non-motor seizures per hour of 2-15 s duration as monitored by electrocorticography. Clinically effective anti-absence drugs were observed to reduce seizure occurrence in a dose-dependent manner. Paradoxically, GABA agonists increased seizure occurrence while GABA antagonists decreased seizure occurrence. Evaluation of the benzodiazepines, diazepam and clonazepam, in this model revealed inhibition of seizure activity by GABA-independent mechanisms. Valproic acid produced a biphasic effect suggesting a GABA-independent, antiabsence action at low doses and GABAergic augmentation of seizure occurrence at higher doses. The results of this study support the hypothesis that increased GABAergic stimulation may induce inhibitory seizures in absence epilepsy.
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PMID:Paradoxical role of GABA in a chronic model of petit mal (absence)-like epilepsy in the rat. 169 Jan 39

Treatment of Long Evans hooded rats during post-natal brain development with the cholesterol synthesis inhibitor, AY-9944 (AY) results in the occurrence of atypical absence seizures, which are frequent, recurrent, and life-long. AY induced slow spike-and-wave discharges (SSWD) are significantly more frequent and prolonged in female Long Evans rats than males. Three groups of experiments were performed in order to characterize further the AY model of atypical absence seizures, (1) a developmental study was performed to ascertain whether AY-induced seizures appear before or after the onset of puberty; (2) male/female differences in severity of response to AY was determined in order to answer the question whether the gender specificity was a pre- or postpubertal phenomenon; (3) a time course study was done to determine the minimum number of postnatal AY doses needed to induce the life-long atypical absence seizure state. The data indicate that AY-induced atypical absence seizures emerge before the onset of puberty. Further, we show that the gender difference in severity of AY-induced seizures also is a pre-pubertal phenomenon. Finally, a single dose of AY (7.5 mg/kg) administered on post-natal day (P) 5 was sufficient to induce SSWD on the electrocorticogram (ECoG). Our results suggest that sex hormones are important in the AY model, although the exact role of cholesterol derived steroid hormones in the regulation and maintenance of AY induced atypical absence seizures remains to be determined.
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PMID:A chronic model of atypical absence seizures: studies of developmental and gender sensitivity. 1182 15

The ketogenic diet (KD), a treatment for drug-resistant epilepsy, elevates brain acetone. Acetone has been shown to suppress experimental seizures. Whether elevation of acetone is the basis of the anticonvulsant effects of the KD and whether acetone, like the KD, antagonizes many different types of seizures, however, is unknown. This study investigated the spectrum of the anticonvulsant effects of acetone in animal seizure models. Rats were injected with acetone intraperitoneally. Dose-response effects were measured in four different models: (1) the maximal electroshock test, which models human tonic-clonic seizures; (2) the subcutaneous pentylenetetrazole test, which models human typical absence seizures; (3) the amygdala kindling test, which models human complex partial seizures with secondary generalization; and (4) the AY-9944 test, which models chronic atypical absence seizures, a component of the Lennox-Gastaut syndrome. Acetone suppressed seizures in all of the models, with the following ED(50)'s (expressed in mmol/kg): maximal electroshock, 6.6; pentylenetetrazole, 9.7; generalized kindled seizures, 13.1; focal kindled seizures, 26.5; AY-9944, 4.0. Acetone appears to have a broad spectrum of anticonvulsant effects. These effects parallel the effects of the KD. Elevation of brain acetone therefore may account for the efficacy of the KD in intractable epilepsy.
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PMID:Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. 1289 74

A time course study that examined the effects of the female estrous cycle on the chronic slow spike-and-wave discharges (SSWDs), gamma-aminobutyric B receptor (GABA(B)R) binding, and GABA(B)R protein expression was conducted in Long Evans hooded rats treated during development with a cholesterol synthesis inhibitor AY9944 (AY). In addition, a pharmacological study using the hormones progesterone, 17 beta-estradiol, mifepristone (intracellular progesterone receptor antagonist), tamoxifen (intracellular estrogen receptor antagonist), and allopregnanolone (progesterone metabolite) was performed to determine their effects on AY-induced seizures. The data indicate that there is a significant increase in both the duration of SSWD and GABA(B)R binding in the AY model, during the proestrus stage of the estrous cycle, the stage during which the levels of progesterone are at their highest. No changes in GABA(B)R1a or R2 protein levels were observed. In addition, the administration of both progesterone and allopregnanolone exacerbated seizures in the AY model, whereas 17 beta-estradiol attenuated the SSWD duration. Neither mifepristone nor tamoxifen blocked the effects of progesterone and 17 beta-estradiol, respectively, on SSWD duration in the AY model, suggesting that these two sex hormones are working in a manner independent of their intracellular receptors. These data suggest an important role for steroid hormones in the regulation and maintenance of AY-induced atypical absence seizures.
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PMID:Hormonal regulation of atypical absence seizures. 1614 15

AY-9944 (AY) exacerbates chronic recurrent seizures in rats that are analogous to atypical absence epilepsy in humans. The mechanism by which AY affects the slow spike-and-wave discharges associated with these seizures is not known, but is thought to involve inhibition of cholesterol synthesis. We tested the hypothesis that seizures seen with AY are due to significant reduction in brain cholesterol and/or elevated brain 7-dehydrocholesterol by assessing whether three other cholesterol synthesis inhibitors mimic AY seizures in rats. Effects of AY on brain sterols and spike-and-wave discharge duration were compared with those of two other late-stage cholesterol inhibitors [BM 15.766 (BM) and U18666A (UA)] and to an HMG-CoA reductase (early-stage cholesterol) inhibitor, lovastatin. With BM or UA, prolongation of seizure duration and brain sterol changes was similar to that caused by AY. AY effects on both brain sterols and seizure duration were dose-related. Lovastatin, with or without concurrent AY, mimicked AY seizures but reduced brain cholesterol by <10% and did not significantly change brain 7-dehydrocholesterol. Either lovastatin has a different mechanism of action than these late-stage cholesterol inhibitors or the brain sterol changes are not directly responsible for seizures in this model.
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PMID:Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols. 1531 96

Medically refractory seizure disorders in children usually have malignant neurodevelopmental outcomes and often are associated with the presence of congenital cortical dysplasias in the brain. To date, there are no animal models of these disorders by which to test hypotheses of pathogenesis or to screen novel drugs for antiepileptic activity. In rats, treatment with the antimitotic agent methylazoxymethanol acetate (MAM) on gestational day (G) 15 produces a neuronal migration disorder similar to the cortical dysplasias seen in human brain. We sought to produce chronic, recurrent, medically refractory seizures by administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during postnatal development in rats exposed prenatally to MAM. Prenatal MAM and postnatal AY treatments resulted in spontaneous, recurrent atypical absence seizures that were characterized by bilaterally synchronous slow spike-and-wave discharges (SWD) with a frequency of 6 Hz. The MAM-AY-induced seizures were refractory to ethosuximide, sodium valproate, and the GABABR antagonist CGP 35348, and were exacerbated by carbamazepine. Histological examination of brains from MAM-treated rats showed hippocampal heterotopias, in addition to atrophy and abnormalities of cortical lamination. The MAM-AY-treated rat represents a reproducible model of refractory atypical absence seizures in children with brain dysgenesis.
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PMID:Refractory atypical absence seizures in rat: a two hit model. 1551 32

Atypical absence seizures (AASs) represent a pediatric malignant seizure type that commonly exists as a component of Lennox-Gastaut syndrome. AAS involves both the hippocampal and thalamocortical circuitry in slow spike-and-wave discharges (SSWD) and is associated with cognitive dysfunction. The electrographic, behavioral, and pharmacological features of clinical AAS have been reproduced in rats chronically in the AY-9944 (AY) model. AY rats show spontaneous SSWD involving the hippocampus, a structure that is highly implicated in learning and memory. The purpose of the present study was to determine whether AY rats exhibit cognitive deficits that mirror those observed in AAS clinically. Hippocampal function was examined in AY animals both in vitro with electrophysiology (i.e., synaptic plasticity) and in vivo with a hippocampus-dependent radial arm maze (RAM) task that is designed to assess spatial cognition. In vitro tests of synaptic plasticity revealed impairments in long-term potentiation (LTP), paired-pulse facilitation (PPF), and presynaptic depression (PD). Consistently, performance of AY animals in RAM revealed fewer perfect entries, a greater number of errors, and required more training days to learn the task than saline-treated controls. The abolishment of spontaneous seizures by ethosuximide failed to recover the perturbed spatial learning and working memory in AY animals. AY rats demonstrate altered hippocampal functioning as manifested by altered synaptic plasticity and cognition. The relationship between AAS and cognitive deficit remains uncertain and the pathophysiology of both in AY treated requires further investigation.
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PMID:Learning and memory impairment in rats with chronic atypical absence seizures. 1553 Aug 72

Chronic atypical absence seizures are a component of the Lennox-Gastaut syndrome, a disorder invariably associated with severe cognitive impairment in children. However, the cause of this intellectual delay remains unclear. The AY9944 model of chronic atypical absence seizures in rats reliably reproduces the electrographic, behavioral, pharmacological and cognitive features of clinical atypical absence. Using this model, we tested the hypothesis that the cognitive impairment associated with this disorder involves a gamma-aminobutyric acid B (GABA(B)) receptor-mediated mechanism. Therefore, we examined the effect of a specific, high affinity GABA(B) receptor antagonist, CGP35348, on the atypical absence seizures, the working memory deficits, and the altered long-term potentiation that we have observed in the AY9944 model. CGP35348 blocked atypical absence seizures, restored long-term potentiation to normal level, and reversed the cognitive deficit in the AY9944-treated animals. However, dose-response studies showed that lower doses of CGP35348 that failed to influence atypical absence seizure activity, completely reversed the spatial working memory deficit. These data suggest that GABA(B) receptor-mediated mechanisms are responsible for the cognitive dysfunction in the AY9944 model of chronic atypical absence seizures and further, that their cognitive impairment is independent of the seizure activity. The data raise the possibility that GABA(B) receptor antagonists may have therapeutic potential for the treatment of cognitive impairment in epilepsy syndromes where atypical absence seizures are a component.
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PMID:GABAB receptor antagonism abolishes the learning impairments in rats with chronic atypical absence seizures. 1676 40

We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY) during early postnatal development. Chronic atypical absence seizures were verified in the AY-treated animals by the presence of spontaneous 5- to 6-Hz slow spike-wave discharges (SSWDs) in the neocortex. General behavioral activity, as measured by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), and rotational behavior (TURNS), were continuously recorded under a 12-hour light:12-hour dark photocycle. The average SSWD duration in AY-treated rats varied daily, with two peaks occurring at approximately dark phase and light phase onset. Mice treated with AY exhibited significant increases in all behavioral measures during the light and dark phases, with the exception of light-phase CT, which did not differ from that of controls. Consequently, the daily rhythm of total behavioral activity (TM) exhibited a significantly higher mean oscillation (mesor) and amplitude without evidence of phase shift compared with the TM rhythm of controls. The occurrence of SSWD activity in the AY model appears to be subject to regulation by biological timing mechanisms and, furthermore, associated with motor hyperactivity that does not alter the timing of behavioral rhythmicity.
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PMID:Daily rhythms of seizure activity and behavior in a model of atypical absence epilepsy. 1703 24


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