RESUMEN
This study tightly controlled seizure duration and severity during status epilepticus (SE) in postnatal day 10 (P10) rats, in order to isolate hyperthermia as the main variable and to study its consequences. Body temperature was maintained at 39 ± 1 °C in hyperthermic SE rats (HT+SE) or at 35 ± 1 °C in normothermic SE animals (NT+SE) during 30 min of SE, which was induced by lithium-pilocarpine (3 mEq/kg, 60 mg/kg) and terminated by diazepam and cooling to NT. All video/EEG measures of SE severity were similar between HT+SE and NT+SE pups. At 24h, neuronal injury was present in the amygdala in the HT+SE group only, and was far more severe in the hippocampus in HT+SE than NT+SE pups. Separate groups of animals were monitored four months later for spontaneous recurrent seizures (SRS). Only HT+SE animals developed convulsive SRS. Both HT+SE and NT+SE animals developed electrographic SRS (83% vs. 55%), but SRS frequency and severity were higher in hyperthermic animals (12.5 ± 3.5 vs. 4.2 ± 2.0 SRS/day). The density of hilar neurons was lower, thickness of the amygdala and perirhinal cortex was reduced, and lateral ventricles were enlarged in HT+SE over NT+SE littermates and HT/NT controls. In this model, hyperthermia greatly increased the epileptogenicity of SE and its neuropathological sequelae.
Asunto(s)
Encéfalo/patología , Encéfalo/fisiopatología , Hipertermia Inducida/efectos adversos , Degeneración Nerviosa/etiología , Estado Epiléptico/etiología , Adyuvantes Inmunológicos/toxicidad , Animales , Animales Recién Nacidos , Anticonvulsivantes/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/ultraestructura , Muerte Celular/efectos de los fármacos , Diazepam/uso terapéutico , Modelos Animales de Enfermedad , Cloruro de Litio/toxicidad , Masculino , Agonistas Muscarínicos/toxicidad , Neuronas/patología , Neuronas/ultraestructura , Neurópilo/patología , Neurópilo/ultraestructura , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABAA (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABAA receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.
Asunto(s)
Encéfalo/metabolismo , Encéfalo/fisiopatología , Neuropéptidos/metabolismo , Receptores de GABA-A/metabolismo , Receptores de Glutamato/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatología , Animales , Anticonvulsivantes/farmacología , Encéfalo/efectos de los fármacos , Resistencia a Medicamentos/fisiología , Humanos , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatología , Receptores de GABA-A/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Estado Epiléptico/tratamiento farmacológico , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Status epilepticus (SE) describes an enduring epileptic state during which seizures are unremitting and tend to be self-perpetuating. We describe the clinical phases of generalized convulsive SE, impending SE, established SE, and subtle SE. We discuss the physiological and biochemical cascades which characterize self-sustaining SE (SSSE) in animal models. At the transition from single seizures to SSSE, GABA(A) (gamma-aminobutyric acid) receptors move from the synaptic membrane to the cytoplasm, where they are functionally inactive. This reduces the number of GABA(A) receptors available for binding GABA or GABAergic drugs, and may in part explain the development of time-dependent pharmacoresistance to benzodiazepines and the tendency of seizures to become self-sustaining. At the same time, 'spare' subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors move from subsynaptic sites to the synaptic membrane, causing further hyperexcitability and possibly explaining the preserved sensitivity to NMDA blockers late in the course of SE. Maladaptive changes in neuropeptide expression occur on a slower time course, with depletion of the inhibitory peptides dynorphin, galanin, somatostatin and neuropeptide Y, and with an increased expression of the proconvulsant tachykinins, substance P and neurokinin B. Finally, SE-induced neuronal injury and epileptogenesis are briefly discussed.
Asunto(s)
Estado Epiléptico/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Neuronas/fisiología , Receptores de GABA/fisiología , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We examined the mechanism of neuronal necrosis induced by hypoxia, excitotoxicity or non-excitotoxic hypoxia. Our observations showed that neuronal necrosis can be an active process starting with early mitochondrial swelling, followed by cytochrome c release and caspase cascade. Energy failure and/or calcium overloading of mitochondria may trigger this sequence of events. We called this form of necrosis 'programmed necrosis'. We discuss in this paper the contribution of another mitochondrial death factor, apoptosis-inducing factor.
Asunto(s)
Mitocondrias/fisiología , Neuronas/patología , Isquemia Encefálica/patología , Caspasas/metabolismo , Humanos , Hipoxia Encefálica/patología , Modelos Neurológicos , NecrosisRESUMEN
When excitotoxic mechanisms are blocked, severe or prolonged hypoxia and hypoxia-ischemia can still kill neurons, by a mechanism which is poorly understood. We studied this "non-excitotoxic hypoxic death" in primary cultures of rat dentate gyrus neurons. Many neurons subjected to hypoxia in the presence of blockers of ionotropic glutamate receptors developed the electron microscopic features of necrosis. They showed early mitochondrial swelling, loss of mitochondrial membrane potential and cytoplasmic release of cytochrome c, followed by activation of caspase-9, and by caspase-9-dependent activation of caspase-3. Caspase inhibitors were neuroprotective. These results suggest that "non-excitotoxic hypoxic neuronal death" requires the activation in many neurons of a cell death program originating in mitochondria and leading to necrosis.
Asunto(s)
Caspasas/metabolismo , Giro Dentado/citología , Hipoxia , Neuronas/metabolismo , Neuronas/patología , Adenosina Trifosfato/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática , Hipoxia/metabolismo , Hipoxia/patología , Hipoxia/fisiopatología , L-Lactato Deshidrogenasa/metabolismo , Microscopía Electrónica de Transmisión/métodos , Microscopía Inmunoelectrónica/métodos , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Necrosis , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Fármacos Neuroprotectores/farmacología , Quinoxalinas/farmacología , Ratas , Cianuro de Sodio/toxicidadRESUMEN
The potential induction of neuronal death by neuroactive drugs at specific stages of embryonic or postnatal development is a serious concern in treating brain disease. Recent evidence indicates that NMDA antagonists, GABA agonists, ethanol and some anesthetics can all produce massive neuronal cell loss at critical times during development. We show here that the anesthetic urethane, once used clinically, produces a selective lesion of the piriform cortex, a region not previously implicated in such toxicity, in the developing brain. Young rats were injected with urethane at 1, 2, 3, and 4 weeks of age and brain damage was measured 1-4 days later. We found that urethane produces a large lesion in subfields of the piriform cortex and that the damage is most severe in 2 week-old animals. These data, together with other recent reports, show that there are multiple neuronal death-inducing pathways in the developing nervous system. It will be important to determine if anesthetics used in pregnant women and young children may have similar effects.
Asunto(s)
Anestésicos Intravenosos/toxicidad , Vías Olfatorias/efectos de los fármacos , Vías Olfatorias/crecimiento & desarrollo , Uretano/toxicidad , Factores de Edad , Animales , Vías Olfatorias/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Mycobacterium abscessus is a ubiquitous, saprophytic organism with low pathogenic potential. The authors describe the previously unreported clinical features of meningitis and native valve endocarditis caused by this rapidly growing atypical mycobacterium. The fatal outcome of this unusual case coincides with the grim prognosis of this disseminated infection and the significant mortality rate associated with neurologic complications of infective endocarditis.
Asunto(s)
Encéfalo/patología , Infecciones por Mycobacterium/patología , Mycobacterium/aislamiento & purificación , Adulto , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
Substance P, which modulates synaptic excitability, can be induced by a variety of stimuli. We studied the expression of hippocampal substance P in rats in using lithium-pilocarpine model of status epilepticus during development. Status epilepticus resulted in an age-specific manner of substance P expression that was anatomically distinctive in hippocampal subfields. Maximal induction of substance P immunoreactivity was seen in the CA1 region of the two-week-old rats, and progressively decreased in the three-, four-week-old rats and adults. Meanwhile, the number of substance P-immunoreactive neurons in the CA3 region and dentate granule cell layer was minimal in the two-week-old animals, but approximated the adult level in the three- and four-week-old rats. No substance P-immunoreactive axon terminals were seen in the strata pyramidale and lucidum in the CA3 region of the two-week-old rats, but they were found to progressively increase in the three-, four-week-old rats and adults. To confirm substance P expression after status epilepticus, we studied the expression of preprotachykinin-A mRNA in the hippocampus of the three-week-old rats by in situ hybridization. Two hours following injection of lithium-pilocarpine, preprotachykinin-A mRNA dramatically increased in the granule cells, as well as in the CA3 and CA1 pyramidal cell layers of the hippocampus. To evaluate the relationship between behavioral seizures and substance P induction, we used the NMDA receptor antagonist MK-801. Injection of MK-801 completely blocked lithium-pilocarpine-induced behavioral seizures and SP induction in the two-week-old rats. These results indicate that seizure activity selectively evokes age-dependent and region-selective expression of substance P.
Asunto(s)
Hipocampo/crecimiento & desarrollo , Neuronas/metabolismo , Estado Epiléptico/metabolismo , Sustancia P/metabolismo , Factores de Edad , Animales , Maleato de Dizocilpina/farmacología , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Cloruro de Litio/efectos adversos , Masculino , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/patología , Pilocarpina/efectos adversos , Precursores de Proteínas/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/patología , Taquicininas/metabolismoRESUMEN
Although epilepsy often begins in childhood, factors that contribute to the development of epilepsy as a consequence of status epilepticus (SE) during early development are poorly understood. We investigated animal models in which seizure-induced epileptogenicity could be studied. Rats undergoing self-sustaining SE induced by perforant path stimulation (PPS) at the ages of postnatal day 21 (P21) and P35 were compared with those subjected to SE by lithium and pilocarpine (LiPC). Although only one animal subjected to PPS at P21 developed chronic spontaneous seizures by several months of observation, all the animals subjected to PPS at P35 became epileptic. In the LiPC model, however, most of the rat pups subjected to SE at P21 became epileptic. Animals with spontaneous seizures showed increased inhibition in the dentate gyrus, a characteristic of the epileptic brain, with evidence of mossy fiber synaptic reorganization. Examination of circuit recruitment by c-Jun immunohistochemistry showed activation restricted to the hippocampus in P21 animals subjected to PPS, although extensive activation of hippocampal and extrahippocampal structures was seen in pups subjected to PPS-induced self-sustaining SE at P35 or LiPC SE at P21. These results demonstrate that the appearance of epilepsy as a consequence of SE is influenced by the type of insult as well as by age-dependent circuit recruitment.
Asunto(s)
Envejecimiento/fisiología , Fibras Musgosas del Hipocampo/patología , Plasticidad Neuronal/fisiología , Estado Epiléptico/patología , Estado Epiléptico/fisiopatología , Animales , Modelos Animales de Enfermedad , Inmunohistoquímica , Fibras Musgosas del Hipocampo/fisiopatología , Ratas , Ratas WistarRESUMEN
PURPOSE: Several experimental paradigms of seizure induction that produce epilepsy as a consequence have been shown to be associated with the proliferation of dentate granule cells. In developing animals, the acute sequela of hilar damage and the chronic sequelae of spontaneous seizures and mossy fiber synaptic reorganization, in response to status epilepticus, occur in an age-dependent manner. We investigated seizure-induced granule cell neurogenesis in developing rat pups to study the association between hilar injury, granule cell neurogenesis, and epilepsy. METHODS: Rat pups of 2 and 3 weeks postnatal age were subjected to lithium-pilocarpine status epilepticus (LiPC SE). Rats were given bromodeoxyuridine (BrdU; 50 mg/kg intraperitoneal) twice daily for 4 days beginning 3 days after SE to label dividing cells. Routine immunocytochemistry and quantification of BrdU labeling by image analysis were performed. Results were compared with previously reported data on cellular injury, mossy fiber sprouting, and spontaneous seizures in rat pups of these ages after LiPC SE. RESULTS: In 3-week-old pups, which demonstrate SE-induced hilar damage and develop spontaneous seizures accompanied by mossy fiber sprouting, the BrdU-immunoreactive area (percent) in the subgranular proliferative zone increased to 10.6 +/- 2.5 compared with 1.4 +/- 0.5 in the control animals (p < 0.05). The 2-week-old animals, which show neither hilar damage nor sprouting and rarely develop spontaneous seizures, also showed a comparable extent of SE-induced neurogenesis [8.0 +/- 1.4 (LiPC SE) versus 0.4 +/- 0.2 (control), p < 0.05]. CONCLUSIONS: Seizure-induced granule cell neurogenesis does not appear to be a function of seizure-induced hilar cellular damage. Granule cell neurogenesis induced by SE does not determine epileptogenesis in the developing rat.
Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/fisiopatología , Hipocampo/citología , Hipocampo/fisiopatología , Plasticidad Neuronal , Estado Epiléptico/inducido químicamente , Animales , División Celular/fisiología , Giro Dentado/citología , Giro Dentado/fisiopatología , Estimulación Eléctrica , Inyecciones Intraperitoneales , Litio , Fibras Musgosas del Hipocampo/fisiología , Vía Perforante/fisiología , Pilocarpina , Ratas , Ratas Wistar , Estado Epiléptico/fisiopatologíaRESUMEN
We describe a model of self-sustaining status epilepticus (SSSE) induced by stimulation of the perforant path in free-running rats. In this model, seizures can be transiently suppressed by intrahippocampal injection of a blocker of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/ kainate synapses but return in the absence of further stimulation when the drug ceases to act. However, seizures are irreversibly abolished by blockers of N-methyl-D-aspartate receptors given locally or systemically. SSSE is enhanced by substance P and its agonists and blocked by its antagonists. SSSE induces novel expression of substance P-like immunoreactivity in hippocampal principal cells. These changes and those in other limbic peptides may contribute to the maintenance of SSSE and to the modulation of hippocampal excitability during epileptic seizures. NMDA
Asunto(s)
Plasticidad Neuronal , Neurotransmisores/fisiología , Receptores de Glutamato/fisiología , Estado Epiléptico/fisiopatología , Sustancia P/fisiología , Factores de Edad , Animales , Anticonvulsivantes/farmacología , Diazepam/farmacología , Modelos Animales de Enfermedad , Electroencefalografía/estadística & datos numéricos , Electrochoque , Hipocampo/fisiología , Hipocampo/fisiopatología , Vía Perforante/fisiología , Fenitoína/farmacología , Ratas , Receptores de N-Metil-D-Aspartato/fisiología , Estado Epiléptico/metabolismoRESUMEN
Previous studies have shown that the expression of the neuropeptide galanin in the hippocampus is altered by seizures and that exogenous administration of galanin into the hippocampus attenuates seizure severity. To address the role of endogenous galanin in modulation of hippocampal excitability and its possible role in seizure mechanisms, we studied two types of transgenic mice: mice with a targeted disruption of the galanin gene (GalKO) and mice that overexpress the galanin gene under a dopamine-beta-hydroxylase promoter (GalOE). GalKO mice showed increased propensity to develop status epilepticus after perforant path stimulation or systemic kainic acid, as well as greater severity of pentylenetetrazol-induced convulsions. By contrast, GalOE mice had increased resistance to seizure induction in all three models. Physiological tests of hippocampal excitability revealed enhanced perforant path-dentate gyrus long-term potentiation (LTP) in GalKO and reduced LTP in GalOE. GalKO showed increased duration of afterdischarge (AD) evoked from the dentate gyrus by perforant path simulation, whereas GalOE had increased threshold for AD induction. Depolarization-induced glutamate release from hippocampal slices was greater in GalKO and lower in GalOE, suggesting that alterations of physiological and seizure responses in galanin transgenic animals may be mediated through modulation of glutamate release. Our data provide further evidence that hippocampal galanin acts as an endogenous anticonvulsant and suggest that genetically induced changes in galanin expression modulate both hippocampal excitability and predisposition to epileptic seizures.
Asunto(s)
Galanina/genética , Hipocampo/metabolismo , Convulsiones/genética , Animales , Causalidad , Modelos Animales de Enfermedad , Galanina/metabolismo , Hipocampo/patología , Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Convulsiones/patología , Convulsiones/fisiopatologíaAsunto(s)
Anticonvulsivantes/farmacología , Glicoles de Propileno/farmacología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Felbamato , Glicina/metabolismo , Humanos , N-Metilaspartato/metabolismo , Fenilcarbamatos , Glicoles de Propileno/uso terapéutico , Receptores de Glicina/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Rat pups of ages of 20, 25, 30 and 35 postnatal days were subjected to the perforant-path stimulation model of status epilepticus (SE). This treatment resulted in age- and stimulus-frequency-dependent loss of inhibition in the dentate granule cell layer. Only 35% of the 20-day-old animals, but 88% of the 35-day-olds, progressed to self-sustaining status epilepticus (SSSE). Loss of inhibition as measured by 0.1-Hz paired-pulse testing and histologic damage that extended to the contralateral side, including both the hilus and some extrahippocampal limbic structures, were associated with SSSE. This model of SE differs from in vitro models of SE, in which immature animals show an increased susceptibility to epileptogenic stimuli, and provides us with a novel method to study epileptogenicity in the developing brain.
Asunto(s)
Estado Epiléptico/etiología , Estado Epiléptico/fisiopatología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Animales Recién Nacidos/fisiología , Conducta Animal , Giro Dentado/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estimulación Eléctrica/métodos , Inhibición Neural , Ratas , Ratas Wistar , Estado Epiléptico/patología , Estado Epiléptico/psicologíaRESUMEN
Epileptic seizures are associated with increases in hippocampal excitability, but the mechanisms that render the hippocampus hyperexcitable chronically (in epilepsy) or acutely (in status epilepticus) are poorly understood. Recent evidence suggests that substance P (SP), a peptide that has been implicated in cardiovascular function, inflammatory responses, and nociception, also contributes to hippocampal excitability and status epilepticus, in part by enhancing glutamate release. Here we report that mice with disruption of the preprotachykinin A gene, which encodes SP and neurokinin A, are resistant to kainate excitoxicity. The mice show a reduction in the duration and severity of seizures induced by kainate or pentylenetetrazole, and both necrosis and apoptosis of hippocampal neurons are prevented. Although kainate induced the expression of bax and caspase 3 in the hippocampus of wild-type mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection in the mutant mice. These results indicate that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A null mice are caused by the extinction of a SP/neurokinin A-mediated signaling pathway that is activated by seizures. They suggest that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.
Asunto(s)
Apoptosis , Neurotoxinas/farmacología , Precursores de Proteínas/genética , Proteínas Proto-Oncogénicas c-bcl-2 , Convulsiones/inducido químicamente , Convulsiones/genética , Taquicininas/genética , Animales , Caspasa 3 , Caspasas/metabolismo , Convulsivantes/farmacología , Hipocampo/anatomía & histología , Hipocampo/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Noqueados , Microscopía por Video , Neuronas/efectos de los fármacos , Pentilenotetrazol/farmacología , Precursores de Proteínas/fisiología , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Taquicininas/fisiología , Proteína X Asociada a bcl-2Asunto(s)
Epilepsia/etiología , Epilepsia/patología , Hipocampo/patología , Modelos Neurológicos , Animales , Enfermedad Crónica , Giro Dentado/fisiopatología , Epilepsia/fisiopatología , Interneuronas/fisiología , Excitación Neurológica , Potenciación a Largo Plazo/fisiología , Fibras Musgosas del Hipocampo/fisiopatología , N-Metilaspartato/fisiología , Inhibición Neural , Vías Nerviosas/fisiología , Ratas , Ratas Wistar , Estado Epiléptico/fisiopatología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Status epilepticus remains a life-threatening condition associated with a high mortality. In order to understand the pathophysiological mechanisms underlying sustained seizures, the identification of structures involved in seizure activity allowing to define epileptic networks may be important. Thus, local cerebral metabolic rate for glucose (LCMR(glc)) was measured in a rat model of self-sustaining status epilepticus (SSSE) induced by a brief intermittent perforant path stimulation of 30 min, using the quantitative [(14)C]2-deoxyglucose autoradiographic technique. SSSE induced a generalized bilateral increase in LCMR(glcs) affecting 27 of the 42 structures studied. Largest metabolic increases (>250%) were recorded in the hippocampus, amygdala, entorhinal and piriform cortices, and lateral septum. Marked metabolic activation was also seen in basal ganglia areas such as the substantia nigra, globus pallidus and accumbens nucleus. LCMR(glcs) in brainstem, some midbrain structures, and in the neocortex were not affected by SSSE. In conclusion, a brief stimulation of the hippocampus induced a reproducible limbic SSSE in 100% of the rats, characterized by the metabolic activation of limbic and extralimbic structures, known to be involved in this type of seizures. Therefore, this new model allowing the development of a well-defined SSSE, appears to be particularly suitable for further studies on the mechanisms involved in status epilepticus.
Asunto(s)
Vía Perforante/fisiología , Estado Epiléptico/fisiopatología , Animales , Encéfalo/metabolismo , Desoxiglucosa/metabolismo , Estimulación Eléctrica , Electroencefalografía , Vía Perforante/metabolismo , Ratas , Ratas Wistar , Estado Epiléptico/metabolismoRESUMEN
We examined the effects of blockers of N-methyl-D-asparate (NMDA) and +/- -alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors on the maintenance of self-sustaining status epilepticus (SSSE) induced in rats by brief intermittent electrical stimulation of the perforant path (PPS). Blocking of NMDA receptor at the PCP site by MK-801 (0.5 mg/kg, i.p.) or ketamine (10 mg/kg, i.p.) as well as at the glycine allosteric site by intrahippocampal 5,7-dichlorokynurenic acid (5,7-DCK, 10 nmol), rapidly and irreversibly aborted both behavioral and electrographic manifestation of SSS. Intrahippocampal injection of the AMPA/kainate receptor blocker 6-cyano7-nitroquinixaline-3-dione (CNQX, 10 nmol) transiently suppressed seizures, which reappeared 4-5 h later. We suggest that the maintenance phase of SSSE depends on activation of NMDA receptors and that NMDA receptor blockers may be a promising class of compounds for the treatment of status epilepticus.