RESUMO
Status epilepticus (SE) is a neurological condition that frequently induces severe neuronal injury in the hippocampus, subsequent epileptogenesis and pharmacoresistant spontaneous recurrent seizures (SRS). The repeated administration of LEV (a broad-spectrum antiepileptic drug) during the post-SE period does not prevent the subsequent development of SRS. However, this treatment reduces SE-induced neurodegeneration in the hippocampus. Conversely, propylparaben (PPB) is a widely used antimicrobial that blocks voltage-dependent Na+ channels, induces neuroprotection and reduces epileptiform activity in vitro. The present study attempted to determine if the neuroprotective effects induced by LEV are augmented when combined with a sub-effective dose of PPB. Long-term SE-induced consequences (hyperexcitability, high glutamate release, neuronal injury and volume loss) were evaluated in the hippocampus of rats. LEV alone, as well as combined with PPB, did not prevent the occurrence of SRS. However, animals treated with LEV plus PPB showed high prevalence of low frequency oscillations (0.1-4â¯Hz and 8-90 bands, pâ¯<â¯0.001) and low prevalence of high frequency activity (90-250 bands, pâ¯<â¯0.001) during the interictal period. In addition, these animals presented lower extracellular levels of glutamate, decreased rate of neurodegeneration and a similar hippocampal volume compared to the control conditions. This study's results suggest that LEV associated with PPB could represent a new therapeutic strategy to reduce long-term consequences induced by SE that facilitate pharmacoresistant SRS.
Assuntos
Hipocampo/efeitos dos fármacos , Levetiracetam/farmacologia , Parabenos/farmacologia , Estado Epiléptico/tratamento farmacológico , Tempo , Animais , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Lítio/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pilocarpina/farmacologia , Ratos Wistar , Convulsões/tratamento farmacológico , Estado Epiléptico/induzido quimicamenteRESUMO
Several studies indicate that sodium cromoglycate (CG) induces neuroprotective effects in acute neurological conditions. The present study focused on investigating if the use of CG in rats during the post-status epilepticus (post-SE) period reduces the acute and long-term consequences of seizure activity. Our results revealed that animals that received a single dose of CG (50â¯mg/kg s.c.: subcutaneously) during the post-SE period showed a lower number of neurons in the process of dying in the dentate gyrus, hilus, cornu ammonis 1 (CA1), and CA3 of the dorsal hippocampus than the rats that received the vehicle. However, this effect was not evident in layers V-VI of the sensorimotor cortex or the lateral-posterior thalamic nucleus. A second experiment showed that animals that received CG subchronically (50â¯mg/kg s.c. every 12â¯h for 5â¯days followed by 24â¯mg/kg/day s.c. for 14â¯days using osmotic minipumps) after SE presented fewer generalized convulsive seizures and less neuronal damage in the lateral-posterior thalamic nucleus but not in the hippocampus or cortex. Our data indicate that CG can be used as a therapeutic strategy to reduce short- and long-term neuronal damage in the hippocampus and thalamus, respectively. The data also indicate that CG can reduce the expression of generalized convulsive spontaneous seizures when it is given during the latent period of epileptogenesis.
Assuntos
Cromolina Sódica/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Animais , Cromolina Sódica/farmacologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Estado Epiléptico/fisiopatologia , Fatores de TempoRESUMO
Propylparaben (PPB) induces cardioprotection after ischemia-reperfusion injury by inhibiting voltage-dependent Na+ channels. The present study focuses on investigating whether the i.p. application of 178mg/kg PPB after pilocarpine-induced status epilepticus (SE) reduces the acute and long-term consequences of seizure activity. Initially, we investigated the effects of a single administration of PPB after SE. Our results revealed that compared to rats receiving diazepam (DZP) plus vehicle after 2h of SE, animals receiving a single dose of PPB 1h after DZP injection presented 126% (p<0.001) lower extracellular levels of glutamate in the hippocampus. This effect was associated with an increased potency of low-frequency oscillations (0.1-13Hz bands, p<0.001), a reduced potency of 30-250Hz bands (p<0.001) and less neuronal damage in the hippocampus. The second experiment examined whether the subchronic administration of PPB during the post-SE period is able to prevent the long-term consequences of seizure activity. In comparison to animals that were treated subchronically with vehicle after SE, rats administered with PPB for 5 days presented lower hippocampal excitability and interictal glutamate release, astrogliosis, and neuroprotection in the dentate gyrus. Our data indicate that PPB, when applied after SE, can be used as a therapeutic strategy to reduce the consequences of seizure activity.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Parabenos/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Animais , Contagem de Células , Diazepam/uso terapêutico , Modelos Animais de Doenças , Estimulação Elétrica , Fluoresceínas/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Agonistas Muscarínicos/toxicidade , Fosfopiruvato Hidratase/metabolismo , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologiaRESUMO
Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p < 0.001) and neuronal damage in dentate gyrus, CA1 and CA3. In contrast to SS-SE group, rats from the CG-SE group showed increased latency to the establishment of the status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment.