RESUMO
Ethosuximide was identified as the optimal option for new-onset childhood absence epilepsy (CAE) in a randomized, two-phase dose escalation comparative effectiveness trial of ethosuximide, lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short-term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure-response relationship and to propose model-informed precision dosing guidance. Dose titration occurred over a 16-20-week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4-week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure-response data. Eighty-four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 µg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 µg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model-informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.
Assuntos
Epilepsia Tipo Ausência , Etossuximida , Humanos , Etossuximida/efeitos adversos , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Ácido Valproico/efeitos adversos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamenteRESUMO
N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.
Assuntos
Disfunção Cognitiva , Epilepsia Tipo Ausência , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/complicações , Epilepsia Tipo Ausência/tratamento farmacológico , Humanos , Ratos , Convulsões/induzido quimicamente , Convulsões/complicações , Convulsões/tratamento farmacológicoRESUMO
AIM: Depression is the major psychiatric disorder in patients with epilepsy. Vortioxetine is a novel antidepressant drug for the treatment of major depressive disorders. In the present study, effects of vortioxetine were evaluated in different experimental epilepsy models of rats. MATERIALS AND METHODS: Fifty-six adult male Wistar rats and 28 WAG/Rij rats were divided into 12 groups of 7 rats each. Experiments were conducted with penicillin (500â¯IU, i.c.) and pentylenetetrazole models (50â¯mg/kg, intraperitoneally (i.p.)) in Wistar rats and genetic absence epileptic WAG/Rij rats. The vortioxetine (1, 5, or 10â¯mg/kg, i.p.) was evaluated in these three models. All groups were compared with their control groups. RESULTS: In the penicillin-induced seizure model, 1, 5, or 10â¯mg/kg vortioxetine administration significantly decreased mean spike frequency. In the pentylenetetrazole-induced seizure model, 1, 5, or 10â¯mg/kg vortioxetine demonstrated a significant dose-dependent decrease in mean spike frequency, an increase in the latency to minor and major seizures, and a decrease in total duration of major seizure and convulsion stage. In genetic absence epileptic WAG/Rij rats, 1â¯mg/kg vortioxetine caused no significant alteration in the number and duration of SWDs compared to the controls, while 5 and 10â¯mg/kg doses of vortioxetine increased the number and duration of SWDs. Amplitude of the epileptiform activity did not change in any of the experimental epilepsy models. CONCLUSION: The results of this study suggested that vortioxetine has anticonvulsant activity in penicillin- and pentylenetetrazole-induced seizure models. However, it exhibited proconvulsant activity in the absence epileptic WAG/Rij rats.
Assuntos
Transtorno Depressivo Maior , Epilepsia Tipo Ausência , Animais , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Humanos , Masculino , Penicilinas/toxicidade , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , VortioxetinaRESUMO
AIM: Psychiatric disorders, especially depression and anxiety, are among the most disabling comorbidities in patients with epilepsy, and they are difficult to treat because many antidepressants cause proconvulsive effects. Thus, it is important to identify the seizure risks associated with antidepressants. Trazodone is one of the most frequently prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs for the treatment of depression and anxiety. The aim of the present study was to evaluate the effects of trazodone on epileptiform activity in a penicillin-evoked focal seizure model in Wistar rats and in a genetic absence epilepsy model in Wistar Albino Glaxo/Rijswijk strain (WAG/Rij) rats. METHODS: Trazodone at 5-, 10-, and 30-mg/kg doses was injected intraperitoneally in Wistar rats 30â¯min after penicillin injection, and spike frequency and amplitude of penicillin-induced epileptiform activity were evaluated. In a separate experimental model, the same trazodone doses were injected in WAG/Rij rats to elucidate their effects on number, duration, and amplitude of spike-and-wave discharges (SWDs) and on depression-anxiety like behavior. In both experimental groups, after trazodone injections recordings were made for 3â¯h. Depression-anxiety like behaviors in WAG/Rij rats were examined using forced swim test and open-field test. RESULTS: Trazodone at 10- and 30-mg/kg doses significantly reduced the frequency of penicillin-induced epileptiform activity without changing the amplitude. Trazodone at a 5-mg/kg dose had no effect on either frequency or amplitude of epileptiform activity. Trazodone at all doses significantly increased number and duration of SWDs without changing the amplitude. In addition, all doses of trazodone decreased the number of squares crossed and duration of grooming in open-field test, and reduced swimming time activity and increased immobility time in forced swim test. CONCLUSION: Our results suggest that depending on the dose used, trazodone had an anticonvulsant effect or no effect on penicillin-evoked focal seizure model, but all trazodone doses resulted in proconvulsant and depression-anxiety like behavior in WAG/Rij rats, which represent a genetic absence model of epilepsy.
Assuntos
Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Penicilinas/toxicidade , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Trazodona/administração & dosagem , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/fisiopatologia , Injeções Intraperitoneais , Masculino , Ratos , Ratos Endogâmicos , Ratos Transgênicos , Ratos Wistar , Convulsões/fisiopatologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Trazodona/efeitos adversosRESUMO
Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300⯵g/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300⯵g/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognised neuroprotective properties.
Assuntos
Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Liraglutida/farmacologia , Animais , Anticonvulsivantes/farmacologia , Ansiedade/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Liraglutida/metabolismo , Liraglutida/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/tratamento farmacológicoAssuntos
Anticonvulsivantes/efeitos adversos , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsias Mioclônicas Progressivas/tratamento farmacológico , Piridonas/efeitos adversos , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Epilepsia Tipo Ausência/diagnóstico , Feminino , Humanos , Lactente , Masculino , Nitrilas , Piridonas/uso terapêuticoRESUMO
The loss of glutamate transporter-1 (GLT-1) is associated with temporal lobe epilepsy (TLE). A recent study reported that Hsp90ß interacted with GLT-1 and recruited it to 20S proteasome for degradation. Therefore, inhibiting Hsp90ß may be a new strategy for treating epilepsy. So far, no studies have shown whether the inhibition of Hsp90ß had therapeutic effects on absence epilepsy. Using a model of absence epilepsy, we demonstrated that 17-allylamino-17-demethoxygeldanamycin (17AAG) and Ganetespib (STA9090) had no therapeutic effect. Although this is a negative result, it also has a meaningful exploration value for whether Hsp90 inhibitors have therapeutic effects on other epilepsy types.
Assuntos
Benzoquinonas/farmacologia , Epilepsia Tipo Ausência/tratamento farmacológico , Transportador 2 de Aminoácido Excitatório/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Triazóis/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Benzoquinonas/química , Epilepsia Tipo Ausência/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Lactamas Macrocíclicas/química , Camundongos , Pentilenotetrazol/toxicidade , Triazóis/químicaRESUMO
Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete. Thus, the main aim of this study was the investigation of the effect of uric acid on absence epileptic seizures (spike-wave discharges: SWDs) in a model of human absence epilepsy, the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. We investigated the influence of intraperitoneally (i.p.) injected uric acid (100â¯mg/kg and 200â¯mg/kg), allopurinol (50â¯mg/kg and 100â¯mg/kg), a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10â¯mg/kg) and inosine (500â¯mg/kg) alone and the combined application of allopurinol (50â¯mg/kg) with uric acid (100â¯mg/kg) or inosine (500â¯mg/kg) as well as indomethacin (10â¯mg/kg) with uric acid (100â¯mg/kg) and inosine (500â¯mg/kg) with uric acid (100â¯mg/kg) on absence epileptic activity. We demonstrated that both uric acid and allopurinol alone significantly increased the number of SWDs whereas indomethacin abolished the uric acid-evoked increase in SWD number. Our results suggest that uric acid and allopurinol have proepileptic effects in WAG/Rij rats.
Assuntos
Alopurinol/farmacologia , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Epilepsia Tipo Ausência/induzido quimicamente , Ácido Úrico/farmacologia , Animais , Encéfalo/fisiopatologia , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/fisiopatologia , Masculino , Ratos WistarRESUMO
We describe the case of an elderly woman with an episode of ambulatory de novo absence status epilepticus of late onset (DNASLO) after oral treatment with cefuroxime. A high level of suspicion of DNASLO in cases of unexplained confusion in adults or elderly subjects taking cephalosporins is essential to prompt an emergency EEG and, in turn, rapidly achieve an appropriate diagnosis and enable optimal treatment.
Assuntos
Antibacterianos/efeitos adversos , Cefuroxima/efeitos adversos , Cefalosporinas/efeitos adversos , Epilepsia Tipo Ausência/induzido quimicamente , Estado Epiléptico/induzido quimicamente , Idade de Início , Idoso , Feminino , Humanos , Otite Média/tratamento farmacológicoAssuntos
Anticonvulsivantes/uso terapêutico , Antipsicóticos/efeitos adversos , Demência/tratamento farmacológico , Epilepsia Tipo Ausência/induzido quimicamente , Fumarato de Quetiapina/efeitos adversos , Idoso , Antipsicóticos/uso terapêutico , Demência/diagnóstico , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/fisiopatologia , Feminino , Seguimentos , Humanos , Fenitoína/uso terapêutico , Fumarato de Quetiapina/uso terapêutico , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Ácido Valproico/uso terapêuticoRESUMO
The non-adenosine nucleoside guanosine (Guo) was demonstrated to decrease quinolinic acid(QA)-induced seizures, spontaneously emerged absence epileptic seizures and lipopolysaccharide(LPS)-evoked induction of absence epileptic seizures suggesting its antiepileptic potential. It was also described previously that intraperitoneal (i.p.) injection of 20 and 50mg/kg Guo decreased the number of spike-wave discharges (SWDs) in a well investigated model of human absence epilepsy, the Wistar Albino Glaxo Rijswijk (WAG/Rij) rats during 4th (20mg/kg Guo) and 3rd as well as 4th (50mg/kg Guo) measuring hours. Guanosine can potentially decrease SWD number by means of its putative receptors but absence epileptic activity changing effects of Guo by means of increased extracellular adenosine (Ado) cannot be excluded. An increase in the dose of i.p. injected Guo is limited by its low solubility in saline, therefore, we addressed in the present study whether higher doses of Guo, diluted in sodium hydroxide (NaOH) solution, have more potent antiepileptic effect in WAG/Rij rats. We confirmed that i.p. 50mg/kg Guo decreased but, surprisingly, i.p. 100mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5mg/kg) or a selective Ado A2A receptor (A2AR) antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) (1mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10mg/kg) with 100mg/kg Guo decreased the SWD number compared to i.p. 100mg/kg Guo alone. The results suggest that i.p. 100mg/kg Guo can increase SWD number by means of the adenosinergic system.
Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia Tipo Ausência/induzido quimicamente , Guanosina/efeitos adversos , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia , Análise de Fourier , Indometacina/farmacologia , Lipopolissacarídeos/toxicidade , Antagonistas de Receptores Purinérgicos P1/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Teofilina/farmacologia , Fatores de Tempo , Triazóis/farmacologiaRESUMO
This article reviews the contribution of pharmacologically induced acute and chronic animal models to our understanding of epilepsies featuring non-convulsive generalized seizures, the typical and atypical absence seizures. Typical absences comprise about 5% of all epilepsies regardless of age and the atypical ones are even more common. Although absence epilepsy was thought to be relatively benign, children with childhood epilepsy (CAE) turn out to have a high rate of pretreatment attention deficits that persist despite seizure freedom. The phenomenon of the absence seizure has long attracted research interest because of the clear temporal relationship of the conspicuous EEG rhythm of 3 Hz generalized spike and wave discharges (GSWD) and the parallel transient "loss of consciousness" characterizing these seizures which is time-locked with the GSWD. Indeed, clinical epileptologists, basic scientists and neurophysiologists have long recognized in GSWD a unique electrographic and behavioral marker of the genetic predisposition to most types of epilepsy. Interestingly, the subject is still controversial since it has recently been proposed that both classification terms of CAE currently in use: idiopathic and primary generalized, be abandoned - a point of debate. Both issues - underlying mechanisms and focal origin of absence seizures - may be further enlightened by observations in valid animal models.
Assuntos
Encéfalo/efeitos dos fármacos , Convulsivantes , Modelos Animais de Doenças , Eletroencefalografia/efeitos dos fármacos , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/fisiopatologia , Doença Aguda , Animais , Encéfalo/fisiopatologia , Colinérgicos , Doença Crônica , Antagonistas GABAérgicos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Bloqueadores dos Canais de PotássioRESUMO
We showed previously that the number of spike-wave discharges (SWDs) was increased after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), inosine (Ino) and muscimol alone whereas i.p. guanosine (Guo), uridine (Urd), bicuculline, theophylline and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) alone decreased the SWD number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. These drugs may exert their effects on absence epileptic activity mainly via proinflammatory cytokines-evoked increase in cortical excitability (such as LPS), GABAergic system (LPS, Ino, Urd, muscimol and bicuculline), glutamatergic system (LPS, Guo and MK-801) and adenosinergic system (LPS, Ino, Guo, Urd and theophylline). Both GABAergic system and glutamatergic system are involved in the pathomechanism of absence epilepsy, the LPS-evoked increase in absence epileptic activity and the pro- or antiepileptic effects of non-adenosine (non-Ado) nucleosides Ino, Guo and Urd. Moreover, Ino, Guo and Urd have modulatory effects on inflammatory processes. Thus, we investigated whether Ino, Guo and Urd have also modulatory influence on LPS-evoked increase in SWD number using two different concentrations of each nucleoside in WAG/Rij rats. We demonstrated that Ino dose-dependently aggravated whereas Guo and Urd attenuated the LPS-evoked increase in SWD number. Our results suggest that different nucleosides have diverse effects on LPS-induced changes in absence epileptic activity.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Ribonucleosídeos/farmacologia , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroencefalografia/efeitos dos fármacos , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/fisiopatologia , Masculino , Modelos Animais , Ratos , Ratos WistarRESUMO
BACKGROUND: The aim of this study was to evaluate the effect of carbamazepine (CBZ) upon chemically induced absence seizures and in a genetic absence seizures model in the mouse. METHODS: The γ-butyrolactone (GBL)-induced acute absence seizures and the stargazer spontaneous absence seizures mice models were used to characterize the aggravation of absence seizures induced by oral CBZ treatment. The effect of CBZ upon GABA inward-currents in Ltk cells expressing human recombinant α1ß2γ2, α2ß2γ2, α3ß2γ2 and α5ß2γ2 GABAA receptors was evaluated by means of patch clamp. RESULTS: GBL administration induced motor impairment in NMRI mice. High dose CBZ (25mg/kg body weight) had no effect on motor performance but exacerbated the behavioral incoordination observed for GBL. Also, coadministration of a high dose CBZ and GBL impaired spontaneous locomotion. Moreover, CBZ was investigated after oral administration to evaluate the potential to aggravate GBL-induced acute spike-and-wave discharges (SWD) in the electroencephalogram. High dose CBZ significantly aggravated SWD induced by GBL. Likewise, in the stargazer mouse model of genetic spontaneous absence seizures, CBZ significantly aggravated SWD frequency and duration. Pre-treatment with the T-type Ca(2+) channel blocker ethosuximide (200mg/kg body weight) prevented the CBZ aggravation of SWD induced by GBL and in the stargazer mouse. CBZ increased in a concentration dependent manner sub-maximal α1ß2γ2 and α3ß2γ2 GABA currents. CONCLUSION: CBZ aggravates absence seizures as assessed in two dedicated mouse models of absence seizures. Facilitation of sub-maximal α1ß2γ2, and α3ß2γ2 GABA currents by CBZ may play a role in CBZ-induced GABA-mediated aggravation of absence seizures.
Assuntos
Anticonvulsivantes/toxicidade , Carbamazepina/toxicidade , Epilepsia Tipo Ausência/induzido quimicamente , 4-Butirolactona , Animais , Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/metabolismo , Relação Dose-Resposta a Droga , Eletroencefalografia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Técnicas de Patch-Clamp , Desempenho Psicomotor/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/genéticaRESUMO
Atypical absence epilepsy (AAE) is an intractable disorder characterized by slow spike-and-wave discharges in electroencephalograms (EEGs) and accompanied by severe cognitive dysfunction and neurodevelopmental or neurological deficits in humans. Administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during the postnatal developmental period induces AAE in animals; however, the neural mechanism of seizure development remains largely unknown. In this study, we characterized the cellular manifestations of AY-induced AAE in the mouse. Treatment of brain slices with AY increased membrane excitability of hippocampal CA1 neurons. AY treatment also increased input resistance of CA1 neurons during early postnatal days (PND) 5-10. However, these effects were not observed during late PND (14-21) or in adulthood (7-10 weeks). Notably, AY treatment elicited paroxysmal depolarizing shift (PDS)-like epileptiform discharges during the early postnatal period, but not during late PND or in adults. The PDS-like events were not compromised by application of glutamate or GABA receptor antagonists. However, the PDS-like events were abolished by blockage of voltage-gated Na(+) channels. Hippocampal neurons isolated from an in vivo AY model of AAE showed similar PDS-like epileptiform discharges. Further, AY-treated neurons from T-type Ca(2+) channel α1G knockout (Cav3.1(-/-)) mice, which do not exhibit typical absence seizures, showed similar PDS-like epileptiform discharges. These results demonstrate that PDS-like epileptiform discharges during the early postnatal period are dependent upon Na(+) channels and are involved in the generation of AY-induced AAE, which is distinct from typical absence epilepsy. Our findings may aid our understanding of the pathophysiological mechanisms of clinical AAE in individuals, such as those with Lennox-Gastaut syndrome.
Assuntos
Animais Recém-Nascidos/fisiologia , Modelos Animais de Doenças , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/fisiopatologia , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/efeitos adversos , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Canais de Cálcio Tipo T/deficiência , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/fisiologia , Eletroencefalografia , Epilepsia Tipo Ausência/patologia , Feminino , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Canais de Sódio Disparados por Voltagem/fisiologiaRESUMO
Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms.
Assuntos
Córtex Cerebral/patologia , Epilepsia Tipo Ausência/patologia , Mutação/genética , Receptores de GABA-A/genética , Convulsões Febris/patologia , Potenciais de Ação/genética , Animais , Convulsivantes/toxicidade , Modelos Animais de Doenças , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/genética , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pentilenotetrazol/toxicidade , Convulsões Febris/induzido quimicamente , Convulsões Febris/genética , Estatísticas não Paramétricas , Vibrissas/inervação , Imagens com Corantes Sensíveis à VoltagemRESUMO
Penicillin epilepsy model, whose discharge resembles that of human absence epilepsy, is one of the most useful acute experimental epilepsy models. Though closed-loop optogenetic strategy of interrupting seizures was proved sufficient to switch off epilepsy by controlling thalamus in the post-lesion partial chronic epilepsy model, doubts still exist in absence epilepsy attenuation through silencing thalamus. Here we directly arrested the thalamus to modulate penicillin-induced absence seizures through pseudorandom responsive stimulation on eNpHR-transfected rats. Our data suggested that the duration of epileptiform bursts under light conditions, compared with no light conditions, did not increase or decrease when modulated specific eNpHR-expressing neurons in thalamus.
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Epilepsia Tipo Ausência/induzido quimicamente , Halorrodopsinas/genética , Neurônios/metabolismo , Optogenética , Penicilinas/efeitos adversos , Tálamo/metabolismo , Animais , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/terapia , Masculino , Ratos , TransgenesRESUMO
Typical absence seizures (ASs) are nonconvulsive epileptic events which are commonly observed in pediatric and juvenile epilepsies and may be present in adults suffering from other idiopathic generalized epilepsies. Our understanding of the pathophysiological mechanisms of ASs has been greatly advanced by the availability of genetic and pharmacological models, in particular the γ-hydroxybutyrate (GHB) model which, in recent years, has been extensively used in studies in transgenic mice. GHB is an endogenous brain molecule that upon administration to various species, including humans, induces not only ASs but also a state of sedation/hypnosis. Analysis of the available data clearly indicates that only in the rat does there exist a set of GHB-elicited behavioral and EEG events that can be confidently classified as ASs. Other GHB activities, particularly in mice, appear to be mostly of a sedative/hypnotic nature: thus, their relevance to ASs requires further investigation. At the molecular level, GHB acts as a weak GABA-B agonist, while the existence of a GHB receptor remains elusive. The pre- and postsynaptic actions underlying GHB-elicited ASs have been thoroughly elucidated in thalamus, but little is known about the cellular/network effects of GHB in neocortex, the other brain region involved in the generation of ASs.
Assuntos
Adjuvantes Anestésicos/efeitos adversos , Epilepsia Tipo Ausência/induzido quimicamente , Oxibato de Sódio/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/metabolismo , HumanosRESUMO
Intrinsic burst and rhythmic burst discharges (RBDs) are elicited by activation of T-type Ca(2+) channels in the thalamic reticular nucleus (TRN). TRN bursts are believed to be critical for generation and maintenance of thalamocortical oscillations, leading to the spike-and-wave discharges (SWDs), which are the hallmarks of absence seizures. We observed that the RBDs were completely abolished, whereas tonic firing was significantly increased, in TRN neurons from mice in which the gene for the T-type Ca(2+) channel, CaV3.3, was deleted (CaV3.3(-/-)). Contrary to expectations, there was an increased susceptibility to drug-induced SWDs both in CaV3.3(-/-) mice and in mice in which the CaV3.3 gene was silenced predominantly in the TRN. CaV3.3(-/-) mice also showed enhanced inhibitory synaptic drive onto TC neurons. Finally, a double knockout of both CaV3.3 and CaV3.2, which showed complete elimination of burst firing and RBDs in TRN neurons, also displayed enhanced drug-induced SWDs and absence seizures. On the other hand, tonic firing in the TRN was increased in these mice, suggesting that increased tonic firing in the TRN may be sufficient for drug-induced SWD generation in the absence of burst firing. These results call into question the role of burst firing in TRN neurons in the genesis of SWDs, calling for a rethinking of the mechanism for absence seizure induction.
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Canais de Cálcio Tipo T/metabolismo , Epilepsia Tipo Ausência/fisiopatologia , Núcleos Talâmicos/fisiopatologia , 4-Butirolactona/toxicidade , Potenciais de Ação , Animais , Canais de Cálcio Tipo T/deficiência , Canais de Cálcio Tipo T/genética , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Epilepsia Tipo Ausência/induzido quimicamente , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Técnicas de Patch-ClampRESUMO
We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate.