The anticonvulsant action of midazolam and clonazepam was studied in 168 immature rats in three a... more The anticonvulsant action of midazolam and clonazepam was studied in 168 immature rats in three age groups (12, 18 and 25 days old). Epileptic after-discharges of the spike-and-wave type accompanied by clonic seizures of facial and forelimb muscles induced by stimulation of sensorimotor cortex were used as a model. The solvent used for clonazepam exhibited a tendency to anticonvulsant action in 12-day-old rats. On the contrary, a proconvulsant action was seen in 25-day-old animals. The action of both benzodiazepines was identical and did not change substantially during development. The highest dose used (1 mg kg−1, i.p.) shortened the duration of epileptic after-discharges, the two lower doses (0·1 and 0·02 mg kg−1, i.p.) suppressed the progressive prolongation with repeated stimulations seen under control conditions. Motor correlates of stimulation remained practically uninfluenced by the two benzodiazepines, myoclonic seizures accompanying epileptic after-discharges were attenuated by the highest dose of both drugs.
Advances and technical standards in neurosurgery, 2012
The incidence of epilepsy is at its highest in childhood and seizures can persist for a lifetime.... more The incidence of epilepsy is at its highest in childhood and seizures can persist for a lifetime. As brain tissue from pediatric patients with epilepsy is rarely available, the analysis of molecular and cellular changes during epileptogenesis, which could serve as targets for treatment approaches, has to rely largely on the analysis of tissue from animal models. However, these data have to be analyzed in the context of the developmental stage when the insult occurs. Here we review the current status of the available animal models, the molecular analysis done in these models, as well as treatment attempts to prevent epileptogenesis in the immature brain. Considering that epilepsy is one of the major childhood neurological diseases, it is remarkable how little is known on epileptogenesis in the immature brain at a molecular level. It is a true challenge for the future to expand the armamentarium of clinically relevant animal models, and systematic analysis of molecular and cellular data to enhance the probability of developing syndrome specific antiepileptogenic treatments and biomarkers for acquired pediatric epileptogenesis.
Postictal refractoriness may be taken as an expression of lasting activity of inhibitory systems ... more Postictal refractoriness may be taken as an expression of lasting activity of inhibitory systems arresting seizures. We tested drugs interfering with GABAergic inhibitory system in pairs of cortical epileptic afterdischarges induced with 1-min interval in rats. Under control conditions the second stimulation failed to elicit an afterdischarge. This postictal refractoriness was not affected by antagonists of GABAA receptors acting at three binding sites (bicuculline, picrotoxin, benzodiazepine inverse agonist Ro 19-4603) as well as by a less specific antagonist pentetrazol. In contrast, antagonist of GABAB receptors CGP35348 partially blocked the refractoriness. Cooperation of different inhibitory systems is probably necessary to abolish postictal refractoriness in neocortex. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
The substantia nigra pars reticulata (SNR) controls the spread of seizures. GABA(A)ergic drug (ag... more The substantia nigra pars reticulata (SNR) controls the spread of seizures. GABA(A)ergic drug (agonist or antagonist) infusions into the SNR have age-specific and site-specific effects on flurothyl-induced seizures. Developmental and cell-specific regulation of GABA(A) receptor subunit expression may be responsible for these specific effects. To test this hypothesis, in situ hybridization was used to examine regional expression of alpha1 and gamma2L GABA(A) receptor subunit mRNAs in the SNR during development. Distinct temporal and spatial patterns of expression were observed. In rats at postnatal days (PN) 21-60, fewer neurons were labeled with probes directed to alpha1 and gamma2L subunits in SNRanterior compared with SNRposterior. In addition, neurons in SNRanterior contained higher amounts of hybridization grains than in SNRposterior. In PN 15 rats, the labeling of neurons was relatively diffuse throughout the anterior and posterior SNR regions with moderate amounts of hybridization grains for both subunits. The finding of age-related differential distribution of alpha1 and gamma2L subunit mRNAs in the SNR suggests that GABA(A) receptor heterogeneity may play a role in the age-specific and site-specific effects of GABA(A)ergic agents on seizures in the SNR.
Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA recep... more Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA receptors. Its action in immature animals is not yet sufficiently known therefore we started to study anticonvulsant action of perampanel pretreatment (1-20 mg/kg i.p.) against seizures elicited by pentylenetetrazol. Three age groups of rats were examined - 12, 18 and 25 days old. Perampanel selectively suppressed the tonic phase of generalized seizures in the two younger groups and whole tonic-clonic seizures in the 25-day-old group. It exhibited also an anticonvulsant action against minimal clonic seizures present in control 18- and 25-day-old rats. Perampanel is an effective anticonvulsant drug even at very early stages of brain development.
Cil: Zachvaty a epilepsie jsou spojovany se změnami v mikroRNA (miRNA/miR) profilu mozku. Epileps... more Cil: Zachvaty a epilepsie jsou spojovany se změnami v mikroRNA (miRNA/miR) profilu mozku. Epilepsie casto zapocne v ranem dětstvi kdy je mozek nezralý a neuralni sitě nejsou plně funkcni. Jelikož změny v expresi miRNA můžou ovlivňovat drahy esencialni pro spravný vývoj mozku, může porozuměni dynamiky miRNA u epilepsii s pocatkem v dětstvi napomoci porozuměni mechanizmu vzniku zachvatů a jejich vlivu na vývoj mozku. Cilem teto prace je identifikovat změny v profile miRNA v průběhu epileptogeneze navozene epileptickým statem (SE) u potkanich novorozenců (P12). Metody: Epileptický status byl u potkanů navozen pomoci LiCl/pilokarpinu v dvanactem postnatalnim dni (P12, n=10). Kontrolni zviřata (n=10) podstoupili stejnou proceduru s výjimkou pilokarpinu, který byl nahrazen fyziologickým roztokem. Hipokampalni tkaně byly odebiraný ve třech casových intervalech: 24 hodin (akutni), 7 dnů (latentni) a 3 měsice (chronicke stadium) po SE. Celkova RNA byla izolovana a použita k sekvenaci kratkých RNA za ucelem stanoveni miRNA profilů jednotlivých vzorků. Výsledky: Sekvenacni analýza ukazala, že každe ze zkoumaných stadii epileptogeneze ma unikatni miRNA profil. Exprese větsiny miRNA byla změněna pouze v jednom ze zkoumaných stadii, přicemž hladina miR-155-5p; -22-3p a -24-3p byla zvýsena v akutnim a chronickem stadiu a miRNA-21-5p a -24-2-5p byly zvýseny ve vsech třech stadiich u zviřat po SE. Zavěr: Epilepsie s pocatkem v nezralem mozku vede ke změnam v profile miRNA, ktere můžou zavažně ovlivňovat genovou expresi. Vliv zachvatů na vývoj mozku může být navozen zvýsenim exprese miRNA, charakteristickým pro akutni a chronickou fazi onemocněni, ve kterých dochazi k výskytu zachvatů a epileptických komorbidit
The anticonvulsant action of midazolam and clonazepam was studied in 168 immature rats in three a... more The anticonvulsant action of midazolam and clonazepam was studied in 168 immature rats in three age groups (12, 18 and 25 days old). Epileptic after-discharges of the spike-and-wave type accompanied by clonic seizures of facial and forelimb muscles induced by stimulation of sensorimotor cortex were used as a model. The solvent used for clonazepam exhibited a tendency to anticonvulsant action in 12-day-old rats. On the contrary, a proconvulsant action was seen in 25-day-old animals. The action of both benzodiazepines was identical and did not change substantially during development. The highest dose used (1 mg kg−1, i.p.) shortened the duration of epileptic after-discharges, the two lower doses (0·1 and 0·02 mg kg−1, i.p.) suppressed the progressive prolongation with repeated stimulations seen under control conditions. Motor correlates of stimulation remained practically uninfluenced by the two benzodiazepines, myoclonic seizures accompanying epileptic after-discharges were attenuated by the highest dose of both drugs.
Advances and technical standards in neurosurgery, 2012
The incidence of epilepsy is at its highest in childhood and seizures can persist for a lifetime.... more The incidence of epilepsy is at its highest in childhood and seizures can persist for a lifetime. As brain tissue from pediatric patients with epilepsy is rarely available, the analysis of molecular and cellular changes during epileptogenesis, which could serve as targets for treatment approaches, has to rely largely on the analysis of tissue from animal models. However, these data have to be analyzed in the context of the developmental stage when the insult occurs. Here we review the current status of the available animal models, the molecular analysis done in these models, as well as treatment attempts to prevent epileptogenesis in the immature brain. Considering that epilepsy is one of the major childhood neurological diseases, it is remarkable how little is known on epileptogenesis in the immature brain at a molecular level. It is a true challenge for the future to expand the armamentarium of clinically relevant animal models, and systematic analysis of molecular and cellular data to enhance the probability of developing syndrome specific antiepileptogenic treatments and biomarkers for acquired pediatric epileptogenesis.
Postictal refractoriness may be taken as an expression of lasting activity of inhibitory systems ... more Postictal refractoriness may be taken as an expression of lasting activity of inhibitory systems arresting seizures. We tested drugs interfering with GABAergic inhibitory system in pairs of cortical epileptic afterdischarges induced with 1-min interval in rats. Under control conditions the second stimulation failed to elicit an afterdischarge. This postictal refractoriness was not affected by antagonists of GABAA receptors acting at three binding sites (bicuculline, picrotoxin, benzodiazepine inverse agonist Ro 19-4603) as well as by a less specific antagonist pentetrazol. In contrast, antagonist of GABAB receptors CGP35348 partially blocked the refractoriness. Cooperation of different inhibitory systems is probably necessary to abolish postictal refractoriness in neocortex. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
The substantia nigra pars reticulata (SNR) controls the spread of seizures. GABA(A)ergic drug (ag... more The substantia nigra pars reticulata (SNR) controls the spread of seizures. GABA(A)ergic drug (agonist or antagonist) infusions into the SNR have age-specific and site-specific effects on flurothyl-induced seizures. Developmental and cell-specific regulation of GABA(A) receptor subunit expression may be responsible for these specific effects. To test this hypothesis, in situ hybridization was used to examine regional expression of alpha1 and gamma2L GABA(A) receptor subunit mRNAs in the SNR during development. Distinct temporal and spatial patterns of expression were observed. In rats at postnatal days (PN) 21-60, fewer neurons were labeled with probes directed to alpha1 and gamma2L subunits in SNRanterior compared with SNRposterior. In addition, neurons in SNRanterior contained higher amounts of hybridization grains than in SNRposterior. In PN 15 rats, the labeling of neurons was relatively diffuse throughout the anterior and posterior SNR regions with moderate amounts of hybridization grains for both subunits. The finding of age-related differential distribution of alpha1 and gamma2L subunit mRNAs in the SNR suggests that GABA(A) receptor heterogeneity may play a role in the age-specific and site-specific effects of GABA(A)ergic agents on seizures in the SNR.
Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA recep... more Perampanel is a new antiepileptic drug with unique mechanism of action - antagonism of AMPA receptors. Its action in immature animals is not yet sufficiently known therefore we started to study anticonvulsant action of perampanel pretreatment (1-20 mg/kg i.p.) against seizures elicited by pentylenetetrazol. Three age groups of rats were examined - 12, 18 and 25 days old. Perampanel selectively suppressed the tonic phase of generalized seizures in the two younger groups and whole tonic-clonic seizures in the 25-day-old group. It exhibited also an anticonvulsant action against minimal clonic seizures present in control 18- and 25-day-old rats. Perampanel is an effective anticonvulsant drug even at very early stages of brain development.
Cil: Zachvaty a epilepsie jsou spojovany se změnami v mikroRNA (miRNA/miR) profilu mozku. Epileps... more Cil: Zachvaty a epilepsie jsou spojovany se změnami v mikroRNA (miRNA/miR) profilu mozku. Epilepsie casto zapocne v ranem dětstvi kdy je mozek nezralý a neuralni sitě nejsou plně funkcni. Jelikož změny v expresi miRNA můžou ovlivňovat drahy esencialni pro spravný vývoj mozku, může porozuměni dynamiky miRNA u epilepsii s pocatkem v dětstvi napomoci porozuměni mechanizmu vzniku zachvatů a jejich vlivu na vývoj mozku. Cilem teto prace je identifikovat změny v profile miRNA v průběhu epileptogeneze navozene epileptickým statem (SE) u potkanich novorozenců (P12). Metody: Epileptický status byl u potkanů navozen pomoci LiCl/pilokarpinu v dvanactem postnatalnim dni (P12, n=10). Kontrolni zviřata (n=10) podstoupili stejnou proceduru s výjimkou pilokarpinu, který byl nahrazen fyziologickým roztokem. Hipokampalni tkaně byly odebiraný ve třech casových intervalech: 24 hodin (akutni), 7 dnů (latentni) a 3 měsice (chronicke stadium) po SE. Celkova RNA byla izolovana a použita k sekvenaci kratkých RNA za ucelem stanoveni miRNA profilů jednotlivých vzorků. Výsledky: Sekvenacni analýza ukazala, že každe ze zkoumaných stadii epileptogeneze ma unikatni miRNA profil. Exprese větsiny miRNA byla změněna pouze v jednom ze zkoumaných stadii, přicemž hladina miR-155-5p; -22-3p a -24-3p byla zvýsena v akutnim a chronickem stadiu a miRNA-21-5p a -24-2-5p byly zvýseny ve vsech třech stadiich u zviřat po SE. Zavěr: Epilepsie s pocatkem v nezralem mozku vede ke změnam v profile miRNA, ktere můžou zavažně ovlivňovat genovou expresi. Vliv zachvatů na vývoj mozku může být navozen zvýsenim exprese miRNA, charakteristickým pro akutni a chronickou fazi onemocněni, ve kterých dochazi k výskytu zachvatů a epileptických komorbidit
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