RESUMEN
RATIONALE: Vigabatrin (VGB) is a drug indicated mostly for the treatment of spasms in childhood and West's syndrome patients. This drug inhibits irreversibly the enzyme GABA-transaminase (GABA-T), increasing GABA concentrations and enhancing GABAergic neurotransmission in the brain, which is known to induce behavioral changes. OBJECTIVES: The aims of this study were to evaluate the effects of VGB in the short-term memory (STM), long-term memory (LTM), motivation, locomotion, and exploratory behavior tests and to detect deleterious or protective effects on DNA in target tissues of the drug. METHODS: Male Wistar rats were treated with a single dose of VGB (100, 250, or 500 mg/kg) or saline solution before the inhibitory avoidance and open-field tasks. DNA damage was evaluated using the alkaline comet assay in peripheral blood, cerebral cortex, and hippocampus after behavioral testing. RESULTS: There was no significant difference in the inhibitory avoidance task between the treated groups and the saline group. In all tested doses, VGB reduced the number of rearings in the open-field task. Besides, VGB 500 mg/kg affected locomotion, though it was not able to induce any DNA damage. CONCLUSIONS: VGB did not affect STM and LTM, but the drug impaired the exploration and locomotion likely associated with its sedative effect. In addition, no DNA damage in cortex and hippocampus was detected after behavioral testing, when brain GABA levels are already increased.
Asunto(s)
Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Vigabatrin/farmacología , Animales , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Humanos , Locomoción/efectos de los fármacos , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Motivación/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.
Asunto(s)
Anticonvulsivantes/farmacología , Receptores de GABA/efectos de los fármacos , Receptores de Neurotransmisores/efectos de los fármacos , Convulsiones/fisiopatología , Estado Epiléptico/fisiopatología , Aminas/farmacología , Animales , Ácidos Ciclohexanocarboxílicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Gabapentina , Ácido Glutámico/farmacología , Glutamina/metabolismo , Ketamina/farmacología , Masculino , Agonistas Muscarínicos/toxicidad , N-Metilaspartato/farmacología , Fenobarbital/farmacología , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente , Vigabatrin/farmacología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
It has been established that neurosteroids can either inhibit or enhance GABA(A) receptor activity. Although GABA is the main inhibitory neurotransmitter in the mammalian retina, the effects of neurosteroids on retinal GABAergic activity have not been investigated. The aim of this work was to study the neurochemical and electroretinographic effects of neurosteroids in the golden hamster. On one hand, pregnenolone sulfate inhibited and allotetrahydrodeoxycorticosterone increased GABA-induced [36Cl]- uptake in neurosynaptosomes. On the other hand, in whole retinas, pregnenolone sulfate increased, whereas allotetrahydrodeoxycorticosterone decreased high potassium-induced [3H]GABA release. The effect of both neurosteroids on GABA release was Ca2+-dependent, as in its absence release was not altered. The intravitreal injection of pregnenolone sulfate or vigabatrin (an irreversible inhibitor of GABA degradation) significantly decreased scotopic b-wave amplitude, whereas the opposite effect was evident when bicuculline or allotetrahydrodeoxycorticosterone were injected. A protein with a molecular weight close to that of hamster adrenal cytochrome P450 side-chain cleavage (P450scc) was detected in the hamster retina. P450scc-like immunoreactivity was localized in the inner nuclear and the ganglion cell layers. These results indicate that neurosteroids significantly modulate retinal GABAergic neurotransmission and electroretinographic activity. In addition, the selective localization of P450scc suggests that neurosteroid biosynthesis might occur only in some layers of the hamster retina.
Asunto(s)
Vías Nerviosas/metabolismo , Neuronas/metabolismo , Retina/metabolismo , Esteroides/biosíntesis , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Anticonvulsivantes/farmacología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Corticosterona/análogos & derivados , Corticosterona/farmacología , Cricetinae , Sistema Enzimático del Citocromo P-450/metabolismo , Electrorretinografía/efectos de los fármacos , Antagonistas del GABA/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Mesocricetus , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Pregnenolona/metabolismo , Pregnenolona/farmacología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Retina/efectos de los fármacos , Esteroides/farmacología , Transmisión Sináptica/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Vigabatrin/farmacologíaRESUMEN
OBJETIVO: é relatar a eficácia da vigabatrina no controle das convulsões, bem como as alterações eletrencefalográficas em crianças com esclerose tuberosa e síndrome de West. MÉTODO: Estudo retrospectivo, com dados clínicos, de neuroimagem e de eletrencefalograma. RESULTADOS: Sete pacientes foram acompanhados e o tempo médio de seguimento foi 10 anos. Dos pacientes, quatro eram do sexo feminino e todos eram de cor branca. A média de idade de início das convulsões foi 3,4 meses. Todos usaram associações de vários anticonvulsivantes; no mínimo duas drogas por esquema terapêutico, e cada paciente utilizou pelo menos dois esquemas diferentes. O uso de vigabatrina como monoterapia ou em associação iniciou em média aos 7 anos de idade ou 4 anos após início dos sintomas. Cinco dos sete pacientes que iniciaram vigabatrina ficaram sem crise. CONCLUSÃO: Vigabatrina mostrou-se eficaz no controle das crises, levando a um melhor prognóstico
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Espasmos Infantiles/tratamiento farmacológico , Esclerosis Tuberosa/tratamiento farmacológico , Vigabatrin/uso terapéutico , Edad de Inicio , Anticonvulsivantes/farmacología , Electroencefalografía/efectos de los fármacos , Epilepsia/complicaciones , Estudios de Seguimiento , Pronóstico , Estudios Retrospectivos , Espasmos Infantiles/complicaciones , Resultado del Tratamiento , Esclerosis Tuberosa/complicaciones , Vigabatrin/farmacologíaRESUMEN
Since anticonvulsants have been used for treating neuralgias, an interest has arisen to experimentally test vigabatrin for its gabaergic mechanism of action. For this, 41 Wistar rats were used, and in 25 of them a constractive sciatic neuropathy was induced (Bennet & Xie model). For testing pain symptoms, spontaneous (Scratching) and evoked behaviors to noxious (46 degrees Celsius) and non-noxious (40 degrees Celsius) thermal stimuli were quatified. Moreover, a comparative pharmacological study of vigabatrin with other analgesic anticonvulsant drugs was also performed. The results showed a possible dose-dependent analgesic effect of vigabatrin (gamma-vinyl-GABA) on experimental neuropathic pain, as shown vy the significant (p<0.05) decreasing effect of vigabatrin on scratching and by its significant (p>0.05) increasing effect on the latency of the right hindpaw withdrawal of the animals to noxious thermal stimulus. This was corroborated by similar findings with analgesic anticonvulsants (carbamazepine, phenytoin and valproic acid). This possible and not yet described analgesic effect of vigabatrin seems not to be opioid mediated.