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Query: UMLS:C0596131 (audiogenic seizure)
 315 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article highlights studies in three major domains of potential mechanisms of sudden unexplained death in epilepsy (SUDEP): cardiac, respiratory, and autonomic. Ictal cardiac arrest is a clinically rare but well-recognized potential mechanism of SUDEP. Studies have failed to identify preexisting cardiac electrophysiologic or structural abnormalities that distinguish SUDEP persons. Some degree of pulmonary congestion is a common autopsy finding, but severe pulmonary edema occurs very rarely with seizures. In contrast, periictal apnea and hypoxia occur commonly with generalized tonic-clonic seizures and, to a lesser degree, with complex partial seizures. There are several animal models of postictal respiratory arrest. Postictal respiratory arrest in audiogenic seizure mice can be induced by serotonin receptor inhibition or prevented by selective serotonin reuptake inhibitor (SSRI) drugs. Reduced heart rate variability occurs in patients with refractory epilepsy and can be induced in animal seizure models, but its precise role in predisposing persons to sudden death requires further investigation.
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PMID:What is known about the mechanisms underlying SUDEP? 1908 23

The endogenous neuropeptide galanin and its associated receptors galanin receptor 1 and galanin receptor 2 are highly localized in brain limbic structures and play an important role in the control of seizures in animal epilepsy models. As such, galanin receptors provide an attractive target for the development of novel anticonvulsant drugs. Our efforts to engineer galanin analogs that can penetrate the blood-brain-barrier and suppress seizures, yielded NAX 5055 (Gal-B2), a systemically-active analog that maintains low nanomolar affinity for galanin receptors and displays a potent anticonvulsant activity. In this report, we show that NAX 5055 is active in three models of epilepsy: 1) the Frings audiogenic seizure-susceptible mouse, 2) the mouse corneal kindling model of partial epilepsy, and 3) the 6 Hz model of pharmacoresistant epilepsy. NAX 5055 was not active in the traditional maximal electroshock and subcutaneous pentylenetetrazol seizure models. Unlike most antiepileptic drugs, NAX 5055 showed high potency in the 6 Hz model of epilepsy across all three different stimulation currents; i.e., 22, 32 and 44 mA, suggesting a potential use in the treatment of pharmacoresistant epilepsy. Furthermore, NAX 5055 was found to be biologically active after intravenous, intraperitoneal, and subcutaneous administration, and efficacy was associated with a linear pharmacokinetic profile. The results of the present investigation suggest that NAX 5055 is a first-in-class neurotherapeutic for the treatment of epilepsy in patients refractory to currently approved antiepileptic drugs.
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PMID:Developing novel antiepileptic drugs: characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models. 1933 33

Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K(+)/low Ca(2+) concentration fluid (HKLCF) in rat hippocampal slices. The reduction of HKLCF-induced increases in population spike amplitude was particularly pronounced, and occurred at approximately 10 times lower seletracetam concentrations than previously observed for levetiracetam. These invitro data suggest that desynchronisation of epileptiform activity may contribute significantly to the antiepileptic properties of seletracetam. Seletracetam also showed a potent anti-seizure activity in animal models mimicking partial-onset (kindled animals) and generalized epilepsy (audiogenic seizure susceptible mice and genetic absence epilepsy rats from Strasbourg (GAERS)). In amygdala-kindled rats, seletracetam increased the generalized seizure threshold current and decreased the duration of the after-discharge and the seizure severity observed at the after-discharge threshold current, and generally had a much more potent effect than previously observed for levetiracetam. Seletracetam showed no psychomimetic effects and a very high central nervous system (CNS) tolerability in both kindled and GAERS rats, markedly superior to that of levetiracetam and other antiepileptic drugs. These results suggest that seletracetam may represent an effective and very well tolerated broad-spectrum agent for the symptomatic treatment of epilepsy.
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PMID:Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy. 1938 93

Inhibition of the GABA transporter subtype GAT1 by the clinically available anti-epileptic drug tiagabine has proven to be an effective strategy for the treatment of some patients with partial seizures. In 2005, the investigational drug EF1502 was described as possessing activity at both GAT1 and BGT-1. When combined with the GAT1 selective inhibitor tiagabine, EF1502 was found to possess a synergistic anti-convulsant action in the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy. This effect was subsequently attributed to inhibition of BGT-1. In this study, the anti-convulsant effect of the GAT2/3 inhibitor SNAP-5114 was assessed in the Frings audiogenic seizure-susceptible mouse alone, and in combination with tiagabine and EF1502. The results showed that SNAP-5114 produced a synergistic anti-convulsant effect in combination with EF1502 but not when used in combination with tiagabine. These findings support anatomical evidence that GAT2/3 are most likely located at the synapse in close proximity to GAT1; whereas BGT-1 is located some distance away from the synapse and GAT1 and GAT2/3. Lastly, EF1502 and tiagabine were evaluated alone, and in combination, in the corneal kindled mouse model of partial epilepsy. The results of this evaluation provide further evidence in support of a role for BGT-1 in the control of seizure activity. In addition, they suggest that the combined inhibition of GAT1 and BGT-1 may afford some advantage over inhibiting either transporter alone.
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PMID:Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs. 1939 20

Animal-to-man extrapolation and therapeutic dose prediction are illustrated with two molecules designed to treat epilepsy. Synaptic vesicle protein 2A (SV2A) is the primary molecular target for their anticonvulsive effect, but additional mechanisms may also contribute. Brivaracetam (BRV), currently in phase 3 of clinical development, was used as the benchmark compound. A pharmacokinetic/pharmacodynamic model was built in NONMEM, relating the brain tissue concentrations of BRV in mice and the proportion of animals protected against convulsions in the pharmacological model of audiogenic seizures. Brain concentrations were linked with ex vivo binding to predict brain SV2A occupancy. A physiologically based pharmacokinetic model was developed for predicting BRV concentrations in human plasma and brain tissue. Predicted plasma profiles were in good agreement with observations. Predicted human brain concentrations of BRV and the mouse ex vivo binding pharmacokinetic/pharmacodynamic model were used to extrapolate brain SV2A occupancy at the human therapeutic dose. Secondly, for another compound also exhibiting selective affinity for the same target, similar pharmacokinetic/pharmacodynamic models were built from audiogenic seizure mouse data. Various dosing regimens of the new compound were simulated in order to reach the same brain SV2A occupancy as for the reference compound. These estimations support early development. Assumptions and limitations of the approach are discussed.
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PMID:Physiologically based pharmacokinetic/pharmacodynamic animal-to-man prediction of therapeutic dose in a model of epilepsy. 2010 65

The superior colliculus (SC), substantia nigra pars reticulata (SNPr), and striatum have been characterized as important structures involved in the modulation of seizure activity. In the current study, bicuculline (GABA(A) antagonist) and muscimol (GABA(A) agonist) were microinjected into the deep layers of either the anterior SC (aSC) or posterior SC (pSC) of genetically developed Wistar audiogenic rats. Behavior and EEG activity were studied simultaneously. Only muscimol microinjected into the pSC had behavioral and EEG anticonvulsant effects in Wistar audiogenic rats, eliciting EEG oscillation changes in both SNPr and pSC, primarily during tonic seizures. The SC of Wistar audiogenic rats thus comprises two functionally different subregions, pSC and aSC, defined by distinct behavioral and EEG features. The pSC has proconvulsant audiogenic seizure activity in Wistar audiogenic rats. Our data suggest that this phenomenon may be a consequence of the genetic selection of the Wistar audiogenic rat strain.
Epilepsy Behav 2011 Oct
PMID:Behavioral and EEG effects of GABAergic manipulation of the nigrotectal pathway in the Wistar audiogenic rat strain. 2182 Sep 67

The role of the substantia nigra pars reticulata (SNPr) and superior colliculus (SC) network in rat strains susceptible to audiogenic seizures still remain underexplored in epileptology. In a previous study from our laboratory, the GABAergic drugs bicuculline (BIC) and muscimol (MUS) were microinjected into the deep layers of either the anterior SC (aSC) or the posterior SC (pSC) in animals of the Wistar audiogenic rat (WAR) strain submitted to acoustic stimulation, in which simultaneous electroencephalographic (EEG) recording of the aSC, pSC, SNPr and striatum was performed. Only MUS microinjected into the pSC blocked audiogenic seizures. In the present study, we expanded upon these previous results using the retrograde tracer Fluorogold (FG) microinjected into the aSC and pSC in conjunction with quantitative EEG analysis (wavelet transform), in the search for mechanisms associated with the susceptibility of this inbred strain to acoustic stimulation. Our hypothesis was that the WAR strain would have different connectivity between specific subareas of the superior colliculus and the SNPr when compared with resistant Wistar animals and that these connections would lead to altered behavior of this network during audiogenic seizures. Wavelet analysis showed that the only treatment with an anticonvulsant effect was MUS microinjected into the pSC region, and this treatment induced a sustained oscillation in the theta band only in the SNPr and in the pSC. These data suggest that in WAR animals, there are at least two subcortical loops and that the one involved in audiogenic seizure susceptibility appears to be the pSC-SNPr circuit. We also found that WARs presented an increase in the number of FG+ projections from the posterior SNPr to both the aSC and pSC (primarily to the pSC), with both acting as proconvulsant nuclei when compared with Wistar rats. We concluded that these two different subcortical loops within the basal ganglia are probably a consequence of the WAR genetic background.
Epilepsy Behav 2012 Aug
PMID:Behavioral and EEG effects of GABAergic manipulation of the nigro-tectal pathway in the Wistar audiogenic rat (WAR) strain II: an EEG wavelet analysis and retrograde neuronal tracer approach. 2270 98

Epilepsy is a debilitating disease characterized by recurring seizures. Epilepsy can be studied using animal models, such as rodents prone to audiogenic seizure (AGS), which experience generalized seizures (loss of consciousness accompanied by rhythmic muscle spasms and rigid muscle stiffness) after intense sound stimulation. In 1933, a spontaneous mutation resulting in sensitivity to AGS was observed among laboratory stocks of deer mice (Peromyscus maniculatus artemisiae) at the University of Michigan. Since then, AGS-sensitive deer mice have been maintained as a separate stock, currently housed at the Peromyscus Genetic Stock Center. To further characterize AGS, the authors designed reliable and consistent equipment for inducing and monitoring AGS in deer mice.
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PMID:Improved technique for induction and monitoring of audiogenic seizure in deer mice. 2360 58

DBA/1 mice are susceptible to audiogenic seizure-induced respiratory arrest (S-IRA), leading to death, which is a model of human sudden unexpected death in epilepsy (SUDEP). Female DBA/1 mice exhibited 71% susceptibility to S-IRA on the third daily test when seizure testing began at postnatal day (PND) 24-30, which was slightly (>10%) but not significantly lower than males. When initial seizure testing was delayed (to >7 weeks of age), DBA/1 mice of both sexes exhibited significantly reduced S-IRA susceptibility, as compared to mice tested initially at PND 24-30. These sex and age issues had not been previously evaluated and may be important for the future use of this SUDEP model. We also observed that 30 min after administering a selective serotonin reuptake inhibitor (SSRI), sertraline (40, 50, or 75 mg/kg i.p.), a significantly reduced S-IRA incidence in DBA/1 mice occurred without blocking seizures, which may be relevant to SUDEP prevention.
Epilepsy Behav 2013 Jul
PMID:Effects of age, sex, and sertraline administration on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). 2366 65

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic-clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5-20mg/kg) and VPA (100-300mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30-100mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.
Epilepsy Behav 2013 Sep
PMID:Pharmacological and neuroethological studies of three antiepileptic drugs in the Genetic Audiogenic Seizure Hamster (GASH:Sal). 2387 84


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