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PubMed1993

Cerebral energy metabolism in rats with genetic absence epilepsy is not correlated with the pharmacological increase or suppression of spike-wave discharges.

The quantitative [14C]2-deoxyglucose (2-DG) autoradiographic method was applied to measure the effects of pharmacological agents on local cerebral metabolic rates of glucose (LCMRglcs) in a selected strain of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). In a previous study, we have shown that GAERS display an overall significant increase of LCMRglc compared to non-epileptic rats from a selected strain. To further characterize the metabolic responses in GAERS, we measured the effects of drugs aggravating or suppressing absences. The animals were divided into 4 groups, i.e. 2 non-epileptic control groups and 2 GAERS groups. Ten min before the initiation of the 2-DG procedure, both non-epileptic control and epileptic rats received an injection of the same amount of the pharmacological agent, either haloperidol (2 mg/kg) or ethosuximide (200 mg/kg). In the presence of haloperidol, GAERS exhibited almost continuous spike-wave discharges; however, the difference in energy metabolism between GAERS and non-epileptic control rats was abolished and LCMRglcs were similar in all structures of both groups of animals. In GAERS treated with ethosuximide, spike-wave discharges were totally suppressed, whereas rates of energy metabolism remained higher by 31-72% in all structures of epileptic rats compared to their corresponding non-epileptic controls. These data demonstrate a lack of correlation between the occurrence of spike-wave discharges and LCMRglcs and are in favor of normal or decreased ictal metabolism and of increased interictal glucose utilization by the brain in rats with absence epilepsy.

Action Potentials↗
PubMed2002

Enhancement of spike and wave discharges by microinjection of bicuculline into the reticular nucleus of rats with absence epilepsy.

The aim of this study was to demonstrate the effect of administration of gamma-aminobutyric acid (GABA)(A) receptor antagonist, bicuculline, into the reticular nucleus of the thalamus (nRt) on spike and wave discharges (SWD) and cardiovascular regulation in conscious rats with genetic absence epilepsy. Rats were instrumented with guide cannulas for drug injection and extradural electrodes for electroencephalogram recording. After a 1 week recovery period, iliac arterial catheters were inserted for direct measurement of blood pressure and heart rate. Administration of bicuculline into the nRt produced increases in spontaneous SWD and failed to alter blood pressure and heart rate. These data suggest that GABA(A) receptors located within the nRt are involved in the incidence of SWD, whereas they do not seem to be involved in cardiovascular regulation of rats with genetic absence epilepsy.

Action Potentials↗
PubMed2002

Sequencing of the GRIK1 gene in patients with juvenile absence epilepsy does not reveal mutations affecting receptor structure.

Hereditary factors play a major role in the etiology of juvenile absence epilepsy (JAE) that is a common subtype of idiopathic generalized epilepsy (IGE). Sander et al. [1997: Am J Med Genet 74:416-421] reported an allelic association of JAE with the nine-copy allele of a tetranucleotide repeat polymorphism in the third intron of the kainate-selective GluR5 receptor gene (GRIK1) and supportive evidence for linkage of IGE to GRIK1 in families of JAE probands. These findings suggest that a major genetic determinant of GRIK1 confers susceptibility to JAE. Assuming that the GRIK1 tetranucleotide repeat polymorphism is unlikely to have functional relevance itself, we have sequenced the coding regions and regulatory sequences of the GRIK1 gene in eight JAE patients who carry the nine-repeat allele of the GRIK1 tetranucleotide repeat polymorphism to detect a putative functional GRIK1 mutation that is in linkage disequilibrium with the nine-repeat allele. Seven of them were derived from families showing positive evidence for linkage to GRIK1. Our mutation analysis of coding regions and splice junctions revealed only two silent polymorphisms (A522C and C1173T) out of the five SNPs present in public databases and no mutations affecting protein structure. No significant differences were found in the allele frequencies of the detected polymorphisms between the JAE patients and controls. High levels of sequence conservation were also found in the promoter, in the 5' and both the 3' untranslated regions and in the RNA secondary structure involved in the editing reaction. The results presented indicate that mutations in the coding sequences, in the intron-exon boundaries and in the main regulatory regions of the GRIK1 are not commonly involved in the etiology of JAE.

Adolescent↗
PubMedDate not supplied

Some solvents for antiepileptics have proepileptic potencies in the WAG/Rij rat model for absence epilepsy.

Some solvents for antiepileptics were tested, for 4 consecutive days, in a rat model (the WAG/Rij inbred strain) for absence epilepsy. Electroencephalogram registrations and behavioral observations suggested that both Tween-80 and a mixture of saline/ethanol/propylene glycol caused an increase in the number of epileptic phenomena. This increase was not significant and restricted to injection day 1 with Tween-80 but was significantly present during all 4 injection days with the saline/ethanol/propylene glycol mixture. Furthermore, with this latter solvent the increase became larger during consecutive days. Because of the proepileptic potencies and the differential time effects of these solvents, their usage should be seriously questioned.

Animals↗
PubMed2005

The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy.

We examined the expression and function of group-II metabotropic glutamate (mGlu) receptors in an animal model of absence seizures using genetically epileptic WAG/Rij rats, which develop spontaneous non-convulsive seizures after 2-3 months of age. Six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, ventrobasal thalamic nuclei, and hippocampus, but not in the reticular thalamic nucleus and in the corpus striatum, as assessed by immunohistochemistry and Western blotting. In contrast, mGlu2/3 receptor signalling was reduced in slices prepared from the somatosensory cortex of 6-month-old WAG/Rij rats, as assessed by the ability of the agonist, LY379268, to inhibit forskolin-stimulated cAMP formation. None of these changes was found in "pre-symptomatic" 2-month-old WAG/Rij rats. To examine whether pharmacological activation or inhibition of mGlu2/3 receptors affects absence seizures, we recorded spontaneous spike-wave discharges (SWDs) in 6-month-old WAG/Rij rats systemically injected with saline, the mGlu2/3 receptor agonist LY379268 (0.33 or 1 mg/kg, i.p.), or with the preferential mGlu2/3 receptor antagonist, LY341495 (0.33, 1 or 5 mg/kg, i.p.). Injection of 1mg/kg of LY379268 (1 mg/kg, i.p.) increased the number of SWDs during 3-7 h post-treatment, whereas injection with LY341495 reduced the number of seizures in a dose-dependent manner. It can be concluded that mGlu2/3 receptors are involved in the generation of SWDs and that an upregulation of these receptors in the somatosensory cortex might be involved in the pathogenesis of absence epilepsy.

Age Factors↗
PubMed2000

Genetic variation of the human mu-opioid receptor and susceptibility to idiopathic absence epilepsy.

Pharmacological and autoradiological studies suggest that mu-opioid receptor (OPRM) mediated neurotransmission is involved in the generation of absence seizures. Mutation screening of the human OPRM gene identified a common amino acid substitution polymorphism (Asn40Asp) that differentially modulates the binding affinity of beta-endorphin and signal transduction of the receptor. The present association study tested the candidate gene hypothesis that the Asn40Asp substitution polymorphism in the N-terminal OPRM domain confers genetic susceptibility to idiopathic absence epilepsy (IAE). The genotypes of the Asn40Asp polymorphism were assessed by allele-specific polymerase chain reaction in 72 German IAE patients and in 340 ethnically matched control subjects. The frequency of the Asp40 allele was significantly increased in the IAE patients [f(Asp40) = 0.139] compared to the controls [f(Asp40) = 0.078; chi2 = 5.467, df = 1, P = 0.019; OR = 2.03; 95%-CI: 1.12-3.68]. This allelic association suggests that the functional Asp40 variant of OPRM modulates neuronal excitability underlying the epileptogenesis of IAE.

Alleles↗
PubMed1992

Absence epilepsy: early prognostic signs.

We have studied 124 children with typical absence epilepsy. The onset of symptoms was in 12% under 4 years, in 51% between 4-8 years and in 37% above 8 years. The F:M ratio was 2:1 in children under 4 years versus 1:1 above 8 years. Absences alone occurred in 82% and absences followed or preceded by generalized tonic-clonic seizures (GTCS) in 6.5% and 11%, respectively. Simple absences were not seen in children under 4 years and were more frequent (14%) in the 4-8 years age group. Family history was positive for epilepsy in 20% and febrile convulsion in 7%. Sixteen percent had a positive past history of febrile convulsions. All patients showed bilateral, synchronous spike-wave discharges from 2.5 to 4 c/s. Lateralized spikes, spike-slow wave complexes were found in 27%. Photosensitivity was present in 18% and was marked in 12%. Monotherapy with sodium valproate or ethosuximide (91% SV) was successful in 85% of patients with absences alone and 68% of the absences with GTCS. Only 2% were not fully controlled either on monotherapy or polytherapy. Treatment was withdrawn in 41 patients and 13 relapsed. We have identified four factors associated with relapses: (a) poor initial response to treatment, (b) lateralized focal EEG abnormality and/or marked photosensitivity, (c) the evolution to myoclonic epilepsy, and (d) early withdrawal of AED (< 3 years).

Adolescent↗
PubMed1994

Clinical and genetic aspects of juvenile absence epilepsy.

Fifteen patients aged 11-25 years (mean 15.37, SD 3.89) suffering from juvenile absence epilepsy are presented. Only 3 (20%) had absences (AS) as the only seizure type, 12 (80%) had associated generalized tonic-clinic seizures (GTCS) and in the remaining 3 with absences and GTCS there was also sporadic myoclonus. We found a higher frequency of AS in our patients by clinical history and video-EEG than has been previously reported. In our patients the mean age of onset in years was 11.4, SD 1.24 for AS, 13.12, SD 2.31 for GTCS and 12.5, SD 2.18 for myoclonus. The correct diagnosis was not made on referrals for any of the patients. It took an average of 3-5.5 years from the onset of the AS (range: 6-120 months) and 2 years from the occurrence of GTCS (average: 1-72 months) to make the correct diagnosis and institute proper treatment, which was valproic acid (VPA). The GTCS were controlled in all patients whereas AS continued in 6 (40%), but to a significantly lesser degree. The frequency and the duration of the GTCS before the start of VPA treatment seemed to have an adverse effect on AS control. We documented no circadian rhythm in either AS or the GTCS, except in 2 patients who had AS and GTCS mainly when they awoke in the morning. The sample size was too small to perform a proper genetic study, though a positive history of epilepsies of mixed types was obtained in 35.7% of the parents and the siblings of the probands.

Adolescent↗
PubMed2005

Differential expression of T-type calcium channels in P/Q-type calcium channel mutant mice with ataxia and absence epilepsy.

Mutations in P/Q-type calcium channels generate common phenotypes in mice and humans, which are characterized by ataxia, paroxysmal dyskinesia, and absence seizures. Subsequent functional changes of T-type calcium channels in thalamus are observed in P/Q-type calcium channel mutant mice and these changes play important roles in generation of absence seizures. However, the changes in T-type calcium channel function and/or expression in the cerebellum, which may be related to movement disorders, are still unknown. The leaner mouse exhibits severe ataxia, paroxysmal dyskinesia, and absence epilepsy due to a P/Q-type calcium channel mutation. We investigated changes in T-type calcium channel expression in the leaner mouse thalamus and cerebellum using quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative in situ hybridization histochemistry (ISHH). qRT-PCR analysis showed no change in T-type calcium channel alpha 1G subunit (Cav3.1) expression in the leaner thalamus, but a significant decrease in alpha 1G expression in the whole leaner mouse cerebellum. Interestingly, quantitative ISHH revealed differential changes in alpha 1G expression in the leaner cerebellum, where the granule cell layer showed decreased alpha 1G expression while Purkinje cells showed increased alpha 1G expression. To confirm these observations, the granule cell layer and the Purkinje cell layer were laser capture microdissected separately, then analyzed with qRT-PCR. Similar to the observation obtained by ISHH, the leaner granule cell layer showed decreased alpha 1G expression and the leaner Purkinje cell layer showed increased alpha 1G expression. These results suggest that differential expression of T-type calcium channels in the leaner cerebellum may be involved in the observed movement disorders.

Analysis of Variance↗
PubMed1987

The WAG/Rij rat model for absence epilepsy: age and sex factors.

The effects of age and sex on spontaneously occurring spike-wave complexes in rats of the WAG/Rij strain were studied in 2 experiments. In the first study, 3 independent groups of male rats were tested; the first group at 75 days old, the second at 140 days and the third at 245 days. In the second study, males as well as females were repeatedly tested at the ages of 75, 125 and 175 days. Both experiments indicated an increase with age in the number of spike-waves complexes and in the number of rats with absences. In the second experiment there were no differences detected between males and females at any of the ages. Similarities to and differences with human absence epilepsy are discussed and it is once more concluded that this particular inbred strain may be useful as an additional model of absence epilepsy.

Aging↗
PubMed2006

T-type Ca2+ channels and absence epilepsy.

Burst firing of the thalamic neurons is driven by the low threshold Ca2+ spike generated by Ca2+ influx through T-type Ca2+ channels when these channels are activated by membrane hyperpolarization due to inhibitory inputs. The major inhibitory inputs to the thalamocortical (TC) neurons are from the GABAergic neurons in the thalamic reticular nucleus. Thalamic burst firings have long been implicated in the pathogenesis of absence epilepsy. The recent progress in genetic approaches has provided with an opportunity to examine this issue at the level of an organism. In this review I describe results primarily obtained from the analysis of the mice deficient for the alpha1G locus which is the predominant gene underlying the low threshold Ca2+ currents in the TC neurons. Current results so far demonstrate the essential role of the thalamocortical bursts in certain forms of absence seizures. Understanding of the pathophysiological mechanisms of absence epilepsy may help develop drugs to control the disease.

Animals↗
PubMed2006

Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy.

Neurosteroids are synthesized in the brain and have been demonstrated to modulate various cerebral functions. Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), a naturally occurring neurosteroid, and ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic derivative, are two neurosteroids acting as positive allosteric modulators of the GABA(A) receptor complex acting on a specific steroid recognition site. Both agents antagonize generalized tonic-clonic seizures in various animal models of epilepsy. Pregnenolone sulphate (3beta-hydroxy-5alpha-pregnen-20-one 3-sulphate; PS) is a negative allosteric modulator of GABA(A) receptors and a positive modulator of the NMDA receptors. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were chronically implanted with five frontoparietal cortical electrodes for electrocorticogram (EEG) recordings and bilateral guide cannulae into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs). The focal and bilateral microinjection of the two GABA(A) positive modulators into some thalamic nuclei (nucleus ventralis posteromedialis, nucleus reticularis thalami, nucleus ventralis posterolateralis was usually able to significantly worsen the occurrence of SWDs in WAG/Rij rats. Whereas both compounds were able to reduce the number and duration of SWDs when microinjected into the peri-oral region of the primary somatosensory cortex. The effects of PS were more complex depending on both the dose and the site of administration, generally, at low doses in thalamic nuclei and cortex, PS induced an increase of absence activity and a reduction at higher doses. These findings suggest that neurosteroids might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

Animals↗
PubMed2003

T-type calcium channel gene alpha (1G) is not associated with childhood absence epilepsy in the Chinese Han population.

We investigated whether the T-type calcium channel gene alpha (1G) is associated with childhood absence epilepsy (CAE), a form of idiopathic generalized epilepsy. We carried out direct sequencing of exons 1-37 and the exon-intron boundaries of the alpha (1G) gene in 48 Han Chinese patients with CAE and 48 normal controls. We found no mutation in the exons of alpha (1G). However, we did identify six single nucleotide polymorphisms (SNPs). Using two of these as markers, we carried out a case-control study in 192 patients with CAE and 192 normal controls. The allele and genotype distributions of all the SNPs studied were not significantly different between cases and control groups, thus the alpha (1G) gene is not an important susceptibility gene for CAE, at least in the Chinese population.

Alleles↗
PubMedDate not supplied

[The mapping of spike-wave discharges in WAG/Rij rats (a genetic strain of absence epilepsy)].

The electrical activity of different cortical areas was recorded in 37 WAG/Rij rats under conditions of chronic experiment. The typical for absence epilepsy spike-wave discharges occur in EEG of all the animals of the strain. The average amplitude distribution maps were constructed based on the recording of two main components of the spike-wave discharge. The most frequently occurring discharges of 5-9 s in duration were taken for map construction. Separate maps were constructed for the beginning and for the end a discharge. It was shown that at the beginning of a discharge the maximum of spike amplitude was localized in the frontal cortical area in the site of localization of the eye, vibrissa and chewing movement centers. At the same time, the wave was better pronounced in the occipital cortical areas. At the end of a discharge spike amplitude diminished and the cortical square over which it was manifested was cut down. On the contrary, at the end of a discharge were amplitude increased and the area of its distinct recording spread to the frontal cortical areas. The wave amplitude maximum was observed over the cortical areas 17. The obtained evidence suggest the relatively independent spatio-temporal dynamics of the two main components of the spike-wave discharge complex.

Action Potentials↗
PubMed2001

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: study of the leucine-glutamate cycle.

We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.

Acetates↗
PubMed2006

Common polymorphisms in the CACNA1H gene associated with childhood absence epilepsy in Chinese Han population.

Variants with a relatively high frequency in the CACNA1H gene have previously been identified in cases of childhood absence epilepsy (CAE) in the Chinese Han population most of which are located in exons 6 to 12. In present study we attempted to further investigate whether the CACNA1H gene is associated with CAE. Exons 6 to 12 of CACNA1H gene were sequenced in samples of 100 CAE trios recruited consecutively, and 191 normal human controls. Single nucleotide polymorphisms (SNPs) were studied in both single locus and haplotype analyses in 218 CAE trios, of which 118 trios were selected from our previous research. Case-control comparisons and the transmission disequilibrium test (TDT) both supported a coding SNP (cSNP) rs9934839 (R603R) in exon 9 as being close related to CAE. The carriers of the G allele of rs9934839 had a 3-fold higher risk of CAE than non-carriers. Moreover, another cSNP rs8044363 was predicted to be connected directly with CAE in a Bayesian network. In addition, two haplotypes consisting of five cSNPs in the region of CACNA1H were statistically associated with CAE. Our research provides new evidence to further support the hypothesis that CACNA1H may be an important susceptibility gene for CAE in the Chinese Han population.

Asian People↗
PubMed2002

Rat models of genetic absence epilepsy: what do EEG spike-wave discharges tell us about drug effects?

Electroencephalographic studies in the WAG/Rij rats of Nijmegen and genetic absence epileptic rats of Strasbourg (GAERS), two genetic models for human generalized absence epilepsy, illustrate the usefulness of drug-electroencephalogram (EEG) interaction studies. In the EEG of both types of rats, spontaneously occurring spike-wave discharges are present. For drug discovery, a model with predictive validity is imperative, and both the WAG/Rij and the GAERS models seem adequate. The present paper discusses effects on spike-wave discharges of various compounds that are clinically used. Not only new antiepileptic drugs, such as remacemide, loreclezole, lamotrigine, tiagabine, gabapentin, progabide and levetiracetam are evaluated, but also drugs used for other purposes, such as etomidate and fentanyl-fluanisone for anesthesia, opioidergic drugs and drugs used for strokes. It is shown that some new antiepileptic drugs, such as tiagabine, have spike-wave discharge-increasing properties, while other drugs are worth studying in clinical trials for antiabsence treatment. Furthermore, it is shown that many commonly used drugs such as analgesics, anesthetics and drugs to treat stroke generally enhance spike-wave discharges. It can be concluded that EEG monitoring is imperative for the discovery and development of potentially antiepileptic compounds and that genetic rat models such as the WAG/Rij or GAERS, to a large extent, can reliably predict clinical efficacy of various types of compounds as well as alert us of potentially adverse effects.

Action Potentials↗
PubMedDate not supplied

Valproate in the treatment of absence epilepsy in children: a study of dose-response relationships.

Seven children with absence epilepsy were treated with valproate (VPA). All but one child became free of absence seizures during VPA monotherapy. EEG was recorded for 24 h before start of VPA treatment and repeatedly during treatment. Correlation between plasma VPA concentration and reduction of the number of epileptic discharges was significant. Plasma concentration of 440-660 microM VPA was needed to achieve at least 50% reduction of seizure activity.

Adolescent↗