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1.
Epilepsia ; 55(5): 644-653, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24621352

RESUMO

OBJECTIVE: Temporal lobe epilepsy is a relatively frequent, invalidating, and often refractory neurologic disorder. It is associated with cognitive impairments that affect memory and executive functions. In the rat lithium-pilocarpine temporal lobe epilepsy model, memory impairment and anxiety disorder are classically reported. Here we evaluated sustained visual attention in this model of epilepsy, a function not frequently explored. METHODS: Thirty-five Sprague-Dawley rats were subjected to lithium-pilocarpine status epilepticus. Twenty of them received a carisbamate treatment for 7 days, starting 1 h after status epilepticus onset. Twelve controls received lithium and saline. Five months later, attention was assessed in the five-choice serial reaction time task, a task that tests visual attention and inhibitory control (impulsivity/compulsivity). Neuronal counting was performed in brain regions of interest to the functions studied (hippocampus, prefrontal cortex, nucleus basalis magnocellularis, and pedunculopontine tegmental nucleus). RESULTS: Lithium-pilocarpine rats developed motor seizures. When they were able to learn the task, they exhibited attention impairment and a tendency toward impulsivity and compulsivity. These disturbances occurred in the absence of neuronal loss in structures classically related to attentional performance, although they seemed to better correlate with neuronal loss in hippocampus. Globally, rats that received carisbamate and developed motor seizures were as impaired as untreated rats, whereas those that did not develop overt motor seizures performed like controls, despite evidence for hippocampal damage. SIGNIFICANCE: This study shows that attention deficits reported by patients with temporal lobe epilepsy can be observed in the lithium-pilocarpine model. Carisbamate prevents the occurrence of motor seizures, attention impairment, impulsivity, and compulsivity in a subpopulation of neuroprotected rats.


Assuntos
Atenção , Modelos Animais de Doenças , Epilepsia Parcial Complexa/psicologia , Epilepsia do Lobo Temporal/psicologia , Função Executiva , Estado Epiléptico/psicologia , Animais , Anticonvulsivantes/farmacologia , Atenção/efeitos dos fármacos , Atenção/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Mapeamento Encefálico , Carbamatos/farmacologia , Contagem de Células , Epilepsia Parcial Complexa/induzido quimicamente , Epilepsia Parcial Complexa/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/fisiopatologia , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Inibição Psicológica , Carbonato de Lítio , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Reconhecimento Visual de Modelos/fisiologia , Pilocarpina , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
2.
Epilepsia ; 55(9): 1460-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25059093

RESUMO

OBJECTIVE: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a genetic model, derived from Wistar rats by selective breeding. In all previous studies, GAERS were compared to their paired selected strain not expressing spike-and-wave discharges (SWDs), namely nonepileptic controls (NECs). Because the occurrence/absence of SWDs is of polygenic origin, some other traits could have been selected along with occurrence/absence of SWDs. Therefore, we explored the importance of using a second control group consisting in Wistar rats, the strain of origin of GAERS, in addition to NECs, on locomotion and anxiety in GAERS. METHODS: A test battery encompassing home-cage, open-field, beam-walking and elevated plus-maze evaluations was used. In addition, stereologic analyses were performed to assess the volume of thalamus, amygdala, and hippocampus. The occurrence/absence of SWDs was determined in all three strains by electroencephalography (EEG) recording. RESULTS: When compared to NECs and Wistars, GAERS displayed lower exploratory activity and fastened habituation to novelty. In the plus-maze, scores of GAERS and Wistars were similar, but NECs appeared significantly less anxious (possibly in association with increased amygdala volume); evidence for weaker anxiety in NECs was also found in the open-field evaluation. The volumetric study revealed increased thalamic volume in GAERS compared to both control groups. SWDs were present in all GAERS and in 80% of Wistars. SIGNIFICANCE: Compared to the original Wistar strain as an additional control group, the selective breeding that generated the GAERS has no incidence on anxiety-related behavior, conversely to the selection of SWD suppression in NECs, in which anxiety is attenuated. These findings point to the importance of using a second control group composed of Wistar rats in studies characterizing the behavioral profile of GAERS. Thereby, possible confusions between occurrence/absence of SWDs and other features that come along with selection and/or differential brain development induced by the genetic mutations are reduced.


Assuntos
Ansiedade/etiologia , Epilepsia Tipo Ausência/complicações , Epilepsia Tipo Ausência/genética , Transtornos Neurológicos da Marcha/etiologia , Análise de Variância , Animais , Encéfalo/patologia , Ondas Encefálicas/fisiologia , Modelos Animais de Doenças , Eletroencefalografia , Comportamento Exploratório/fisiologia , Locomoção/genética , Masculino , Aprendizagem em Labirinto , Desempenho Psicomotor/fisiologia , Ratos , Ratos Mutantes , Ratos Wistar
3.
Epilepsia ; 54(7): 1203-13, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23663139

RESUMO

PURPOSE: Administration of carisbamate during status epilepticus (SE) prevents the occurrence of motor seizures in the lithium-pilocarpine model and leads in a subpopulation of rats to spike-and-wave discharges characteristic of absence epilepsy. Widespread neuroprotection accompanied this change in seizure expression. To assess whether these carisbamate-induced changes affected comorbidity, we used a large battery of behavioral tests in rats that had developed temporal lobe or absence-like seizures. METHODS: Lithium-pilocarpine or saline was administered to 60 adult rats. Carisbamate (90 mg/kg) or diazepam and saline was given 1 h after SE onset, and repeated 8 h later and twice daily over 6 more days. Rats were video-monitored for 2 months. Subsequently, locomotor activity, anxiety, and various types of memory were assessed. KEY FINDINGS: In rats with motor seizures, treated or not with carisbamate, all features of behavior were impaired compared to controls. Rats exhibiting absence-like seizures after carisbamate treatment behaved as controls in all paradigms tested along with widespread neuroprotection. SIGNIFICANCE: Carisbamate treatment leading to absence-like instead of temporal lobe seizures impressively prevented behavioral comorbidities reported by patients with epilepsy as the most disabling.


Assuntos
Anticonvulsivantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Carbamatos/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/fisiopatologia , Animais , Antipsicóticos/toxicidade , Encéfalo/patologia , Contagem de Células , Modelos Animais de Doenças , Lítio/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/patologia , Agonistas Muscarínicos/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fosfopiruvato Hidratase/metabolismo , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Percepção Visual/efeitos dos fármacos
4.
Neurobiol Dis ; 41(1): 169-76, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20850530

RESUMO

It is well known that the uncoupling between local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF), i.e. decrease in LCBF rates with high LCGU, is frequently associated with seizure-induced neuronal damage. This study was performed to assess if the neuroprotective effect of the adenosinergic A(1) receptor agonist R-N-phenylisopropyladenosine (R-Pia) injected prior to pilocarpine is able to reduce the uncoupling between LCGU and LCBF during status epilepticus (SE). Four groups of rats were studied: Saline, Pilo, R-Pia+Saline and R-Pia+Pilo. For LCGU and LCBF studies, rats were subjected to autoradiography using [(14)C]-2-deoxyglucose and [(14)C]-iodoantypirine, respectively. Radioligands were injected 4 h after SE onset. Neuronal loss was evaluated by Fluorojade-B (FJB) at two time points after SE onset (24 h and 7 days). The results showed a significant increase in LCGU in almost all brain regions studied in the Pilo and R-Pia+Pilo groups compared to controls. However, in R-Pia pretreated rats, the uncoupling between LCGU and LCBF was moderated in a limited number of structures as substantia nigra pars reticulata and hippocampal formation rather in favor of hyperperfusion. Significant increases in LCBF were observed in the entorhinal cortex, thalamic nuclei, mammillary body, red nucleus, zona incerta, pontine nucleus and visual cortex. The neuroprotective effect of R-Pia assessed by FJB showed a lower density of degenerating cells in the hippocampal formation, piriform cortex and basolateral amygdala. In conclusion our data shows that the neuroprotective effect of R-Pia was accompanied by a compensatory metabolic input in brain areas involved with seizures generation.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Adenosina/análogos & derivados , Circulação Cerebrovascular/efeitos dos fármacos , Glucose/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Adenosina/farmacologia , Animais , Circulação Cerebrovascular/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Estado Epiléptico/metabolismo
5.
Hippocampus ; 20(7): 841-51, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19650120

RESUMO

Longitudinal studies on patients for schizophrenia suggest that functional brain perturbations precede the onset of symptoms. Rats with a neonatal ventral hippocampal lesion (NVHL) are considered as a heuristic neurodevelopmental model of schizophrenia. We characterized basal metabolic changes observed in NVHL rats before and after the age when known behavioral alterations have been reported. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD7). We measured local cerebral metabolic rates for glucose (LCMRglc) by the quantitative autoradiographic [(14)C]2-deoxyglucose technique at pre- (PD21) and postpubertal (PD42) ages when NVHL rats do not express abnormal dopamine related behaviors, and at adulthood (PD70). We observed a widespread increase in LCMRglcs in PD21 NVHL indicative of an ongoing intense reorganization of the brain while at PD42, increases were less extended. At PD70, changes in glucose metabolism were restricted to specific systems, such as the auditory system, the cerebellum, the serotonergic median raphe, and median septum. These data show in a heuristic animal model of schizophrenia that functional metabolic changes within the brain could precede the onset of dopamine-related behavioral alterations and lead to a distinct ensemble of functional changes in adulthood in systems that may be relevant to schizophrenia.


Assuntos
Encéfalo/metabolismo , Hipocampo/lesões , Esquizofrenia/metabolismo , Animais , Animais Recém-Nascidos , Autorradiografia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Glucose/metabolismo , Hipocampo/metabolismo , Masculino , Ratos , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia
6.
Epilepsia ; 51(9): 1829-36, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20633040

RESUMO

PURPOSE: Although the number of antiepileptic drugs (AEDs) is increasing, none displays neuroprotective or antiepileptogenic properties that could prevent status epilepticus (SE)-induced drug-resistant epilepsy. Ketogenic diet (KD) and calorie restriction (CR) are proposed as alternative treatments in epilepsy. Our goal was to assess the neuroprotective or antiepileptogenic effect of these diets in a well-characterized model of mesial temporal lobe epilepsy following initial SE induced by lithium-pilocarpine in adult rats. METHODS: Seventy-five P50 male Wistar rats were fed a specific diet: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), or hypocalorie ketogenic (HK). Rats were subjected to lithium-pilocarpine SE, except six NC to constitute a control group for histology (C). Four rats per group were implanted with epidural electrodes to record electroencephalography (EEG) during SE and the next six following days. From the seventh day, the animals were video-recorded 10 h daily to determine latency to epilepsy onset. Neuronal loss in hippocampus and parahippocampal cortices was analyzed 1 month after the first spontaneous seizure. RESULTS: After lithium-pilocarpine injection, neither KD nor CR modified SE features or latency to epilepsy. In hippocampal layers, KD or CR exhibited a neuroprotective potential without cooperative effect. Parahippocampal cortices were not protected by the diets. CONCLUSION: The antiepileptic effect of KD and/or CR is overwhelmed by lithium-pilocarpine injection. The isolated protection of hippocampal layers induced by KD or CR or their association failed to modify the course of epileptogenesis.


Assuntos
Anticonvulsivantes/farmacologia , Restrição Calórica/métodos , Dieta Cetogênica/métodos , Epilepsia do Lobo Temporal/prevenção & controle , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Carboidratos da Dieta/administração & dosagem , Modelos Animais de Doenças , Resistência a Medicamentos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/estatística & dados numéricos , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Humanos , Cloreto de Lítio , Masculino , Pilocarpina , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente
7.
Int J Neuropsychopharmacol ; 12(8): 1097-110, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19267957

RESUMO

Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.


Assuntos
Regulação da Expressão Gênica/fisiologia , Hipocampo/lesões , Hipocampo/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Estimulação Acústica/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Apomorfina/farmacologia , Calbindina 2 , Calbindinas , Agonistas de Dopamina/farmacologia , Eletroencefalografia/métodos , Feminino , Antagonistas GABAérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato Descarboxilase/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Ibotênico/toxicidade , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Parvalbuminas/metabolismo , Pentilenotetrazol/farmacologia , Ratos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Proteína G de Ligação ao Cálcio S100/metabolismo , Convulsões/induzido quimicamente , Transmissão Sináptica/efeitos dos fármacos
8.
Epilepsia ; 50(1): 33-43, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18657179

RESUMO

PURPOSE: Genetic absence epilepsy rats from Strasbourg (GAERS) are resistant to the progression of kindling seizures. We studied local cerebral blood flow (LCBF) changes in brain regions involved in seizures in both GAERS and nonepileptic rats (NEC) to map the differences that may be related to the resistance to kindling. METHODS: Electrodes were implanted in the amygdala of adult NEC and GAERS male rats, which were stimulated to reach stage 2. Quantitative autoradiographic measurements of LCBF were performed by the [(14)C]-iodoantipyrine ([(14)C]IAP) autoradiographic technique allowing the precise mapping of regional perfusion changes. LCBF rates were measured bilaterally in 43 brain regions. The tracer infusion lasted for 60 s and started at 15 s before seizure induction. RESULTS: Rates of LCBF increased in stimulated GAERS and NEC groups compared to nonstimulated controls. The LCBF increase in stimulated GAERS was larger and more widespread than that observed in stimulated NEC. The LCBF increase in the somatosensory cortex, ventrobasal and anterior thalamic nuclei, hypothalamus, subthalamic nucleus, piriform, entorhinal and perirhinal cortex, amygdala, CA2 region of hippocampus, and substantia nigra was statistically significantly larger in stimulated GAERS compared to stimulated NEC rats. CONCLUSION: The results show that more brain regions are activated by kindling stimulation in GAERS. This widespread activation in GAERS involves the somatosensory cortex and thalamus, which are both known to be involved in the expression of absence seizures as well as numerous limbic regions thought not to play a role in the expression of absence seizures, suggesting an interaction between corticothalamocortical and limbic circuitries.


Assuntos
Encéfalo/irrigação sanguínea , Epilepsia Tipo Ausência/genética , Excitação Neurológica/fisiologia , Animais , Circulação Cerebrovascular/fisiologia , Ratos
9.
Neurobiol Dis ; 31(3): 451-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18638555

RESUMO

The susceptibility of rats with genetically inherited epilepsy to the genesis and consequences of secondary temporal lobe epilepsy is unknown. Here, we induced lithium-pilocarpine status epilepticus (SE) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) or in Wistar audiogenic sensitive (AS) rats. Wistar AS needed less pilocarpine than GAERS and Non-Epileptic Rats (NERs) to develop SE. Sixty six, 40 and 5% of Wistar AS, GAERS and NERs, respectively, died within 24 h after SE. In GAERS, SE prevented the occurrence of absence seizures for 5 days. Thereafter a limited number of absence seizures with low amplitude and short duration were recorded. Wistar AS developed limbic epilepsy within 9 days after SE while GAERS and NERs needed 36-39 days to develop spontaneous motor seizures. Neuronal loss consecutive to SE was similar in the three strains and particularly marked in limbic forebrain and parahippocampal cortices. In conclusion, the development of focal limbic epilepsy in GAERS largely impairs the expression of absence seizures. The genetic background underlying the expression of audiogenic seizures sensitizes strongly the rats to a further insult and compromises their survival.


Assuntos
Epilepsia Tipo Ausência/genética , Epilepsia Reflexa/genética , Epilepsia do Lobo Temporal/genética , Epilepsia/genética , Predisposição Genética para Doença/genética , Estado Epiléptico/genética , Animais , Antimaníacos/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Convulsivantes/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Epilepsia Tipo Ausência/fisiopatologia , Epilepsia Reflexa/induzido quimicamente , Epilepsia Reflexa/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/fisiopatologia , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/fisiopatologia , Compostos de Lítio/farmacologia , Masculino , Agonistas Muscarínicos/farmacologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/genética , Degeneração Neural/fisiopatologia , Giro Para-Hipocampal/efeitos dos fármacos , Giro Para-Hipocampal/fisiopatologia , Pilocarpina/farmacologia , Ratos , Ratos Mutantes , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
10.
J Neurosci Res ; 86(4): 813-20, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17969102

RESUMO

In mice, deletion of the STOP protein leads to subtle anatomic changes and induces depleted synaptic vesicle pools, impaired synaptic plasticity, hyperdopaminergy, and major behavioral disorders alleviated by neuroleptics, hence leading to a schizophrenic-like phenotype. In this study, we applied the quantitative autoradiographic [(14)C]2-deoxyglucose technique to study to what extent the basal rate of cerebral glucose utilization in STOP-knockout (STOP-KO) mice occurs in regions where metabolic changes have been reported in schizophrenic patients. Studies were performed on wild-type, heterozygous, and homozygous STOP-KO mice (7-8 per group). Mice were implanted with femoral artery and vein catheters, and cerebral glucose utilization was quantified over 45 min. Compared with that in wild-type mice, glucose utilization in STOP-KO mice was significantly increased in the olfactory cortex, ventromedial and anterolateral hypothalamus, ventral tegmental area, and substantia nigra pars compacta. Nonsignificant increases, ranging between 9% and 19%, were recorded in the whole auditory system, CA1 pyramidal cell layer, and dorsal raphe. Glucose utilization was also significantly increased in heterozygous mice compared with that in wild-type mice in olfactory cortex. These data might reflect hyperdopaminergic activity, olfactory deficits, and sleep disturbances in STOP-KO mice that have also been reported in schizophrenic patients.


Assuntos
Encéfalo/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Autorradiografia , Glucose/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética
11.
Biomed Mater Eng ; 28(s1): S185-S192, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28372294

RESUMO

The time needed to obtain functional regenerated bone tissue depends on the existence of a reliable vascular support. Current techniques used in clinic, for example after tooth extraction, do not allow regaining or preserving the same bone volume. Our aim is to develop a cellularized active implant of the third generation, equipped with human mesenchymal stem cells to improve the quality of implant vascularization. We seeded a commercialized collagen implant with human mesenchymal stem cells (hMSCs) and then with human umbilical vein endothelial cells (HUVECs). We analyzed the biocompatibility and the behavior of endothelial cells with this implant. We observed a biocompatibility of the active implant, and a re-organization of endothelial cells into clustered networks. This work shows the possibility to develop an implant of the third generation supporting vascularization, improving the medical care of patients.


Assuntos
Colágeno/química , Células Endoteliais da Veia Umbilical Humana/citologia , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Animais , Materiais Biocompatíveis/química , Bovinos , Humanos , Teste de Materiais
12.
J Cereb Blood Flow Metab ; 26(11): 1419-30, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16538232

RESUMO

Glutamate excitotoxicity has been involved in the pathophysiology of epilepsy. Normal functioning of glutamate transporters clears the synaptically released glutamate to prevent excitotoxic neuronal death. Using densitometric immunohistochemical analysis, we examined the temporal expression of the neuronal glutamate transporter (EAAC1) in the lithium-pilocarpine rat model of temporal lobe epilepsy. During the acute period of lithium-pilocarpine-induced status epilepticus, EAAC1 transporter expression increased in the pyramidal neurons of cornus ammonis (CA)1, CA2 and CA3 (fields of the hippocampus), in dentate gyrus (DG) granule cells and in olfactory tubercle (Tu). During the latent period, EAAC1 expression was strongly expressed in the DG granular and molecular layers, Tu, cerebral cortex and septum, and went back to control levels in CA1, CA2 and CA3 layers. The overexpression of EAAC1 occurred mainly in structures prone to develop Fluoro-Jade-B-positive degenerating neurons. It is, however, not clear to what extent the overexpression of EAAC1 contributes to epileptogenesis and in which area it may represent a preventive or compensatory or response to injury.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , Transportador 3 de Aminoácido Excitatório/biossíntese , Cloreto de Lítio , Pilocarpina , Animais , Encéfalo/patologia , Química Encefálica/efeitos dos fármacos , Química Encefálica/fisiologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Fluoresceínas , Imuno-Histoquímica , Degeneração Neural , Compostos Orgânicos , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
13.
Epilepsy Res ; 72(2-3): 147-63, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16945504

RESUMO

Lithium-pilocarpine induces status epilepticus (SE), leading to extensive damage and spontaneous recurrent seizures (SRS). Neuroprotective and antiepileptogenic effects of topiramate (TPM) associated with diazepam (DZP) were investigated in this model. SE was induced by LiCl and pilocarpine. TPM (10, 30 or 60 mg/kg) was injected at the onset of SE and 10h later and DZP (2.5 and 1.25mg/kg) at 2 and 10h after SE. TPM treatment was continued twice daily for 6 days. Other rats received two injections of DZP on the day of SE. Cell counting was performed on thionine-stained sections 14 days after SE and after 2 months of epilepsy. Occurrence and frequency of SRS were video-recorded. The MRI T2-weighted signal was quantified in hippocampus and ventral cortices. DZP-TPM treatment induced partial neuroprotection in CA1 and hilus, and tended to increase the percentage of rats with protected neurons in layer III/IV of the ventral entorhinal cortex. The latency to and frequency of SRS were not modified by DZP-TPM. T2-weighted signal was decreased in hippocampus 3 days after SE at all TPM doses and in ventral hippocampus after epilepsy onset. In conclusion, although DZP-TPM treatment was able to partially protect two areas critical for epileptogenesis, the hippocampus and ventral entorhinal cortex, it was not sufficient to prevent epileptogenesis.


Assuntos
Anticonvulsivantes/uso terapêutico , Diazepam/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Frutose/análogos & derivados , Hipocampo/efeitos dos fármacos , Estado Epiléptico/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Diazepam/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eletroencefalografia/efeitos dos fármacos , Epilepsia do Lobo Temporal/induzido quimicamente , Frutose/farmacologia , Frutose/uso terapêutico , Lítio , Imageamento por Ressonância Magnética , Masculino , Pilocarpina , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Topiramato
14.
Epilepsy Res ; 69(2): 100-18, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16503120

RESUMO

RATIONALE: Measurement of local cerebral blood flow (LCBF) is routinely used to locate the areas involved in the generation and spread of seizures in epileptic patients. Since the spatial distribution and extent of ictal LCBF depends on the epileptogenic network, but also on the timing of injection of tracer, we used a rat model of amygdala kindled seizures to follow time-dependent changes in the distribution of seizure-induced LCBF changes. METHODS: Rats were implanted with a left amygdala electrode and were stimulated until reaching stage 1. LCBF was measured by the quantitative [14C]iodoantipyrine autoradiographic technique. The tracer was injected either at 15 s before seizure induction (early ictal) or simultaneously with the amygdala stimulation (ictal) in rats undergoing a stage 0 or 1 seizure. RESULTS: During stage 0 seizures, LCBF rates increased significantly ipsilaterally in medial and central amygdala and substantia nigra. During stage 1 seizures, LCBF increased unilaterally in amygdala, piriform cortex, substantia nigra, ventral tegmental area and cerebellum and bilaterally in several limbic and subcortical structures, excepted in hippocampus and pallidum. When pooling stages 0 and 1 but considering only tracer injection time, discrete LCBF changes occurred ipsilaterally in amygdala and substantia nigra at early ictal time. At true ictal time, significant changes occurred in several subcortical structures bilaterally while limbic structures displayed more localized and lateralized changes. CONCLUSION: LCBF mapping appears unable to identify in rats the ictal onset zone of clinically significant amygdala-triggered seizures (stage 1), while the study of sub-clinical seizures (stage 0) allowed to correctly locate the amygdala onset of the seizures within the limbic network. Compared to human SPECT studies, this work confirms that some ictal hyperperfused areas belong to the spreading network rather than to the epileptogenic zone. The spatial recruitment of remote subcortical structures could be further investigated to strengthen the rationale of therapeutic stimulation of basal ganglia in drug-resistant epilepsies.


Assuntos
Circulação Cerebrovascular/fisiologia , Epilepsias Parciais/fisiopatologia , Convulsões/fisiopatologia , Tonsila do Cerebelo/patologia , Animais , Antipirina/administração & dosagem , Antipirina/análogos & derivados , Radioisótopos de Carbono/administração & dosagem , Estimulação Elétrica , Eletrodos , Indutores de Interferon/administração & dosagem , Excitação Neurológica , Masculino , Ratos , Ratos Wistar , Convulsões/etiologia , Fatores de Tempo
15.
J Cereb Blood Flow Metab ; 22(2): 196-205, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11823717

RESUMO

Coupling between local cerebral blood flow and local cerebral metabolic rate for glucose is involved in the pathogenesis of epilepsy-related neuronal damage in the adult brain; however, its role in the immature brain is unknown. Lithium-pilocarpine-induced status epilepticus is associated with extended damage in adult rats, mostly in the forebrain limbic areas and thalamus, whereas damage was moderate in 21-day-old rats (P21) or absent in P10 rats. The quantitative autoradiographic [14C]iodoantipyrine technique was applied to measure the consequences of lithium-pilocarpine status epilepticus on local cerebral blood flow. In adult and P21 rats, local cerebral blood flow rates increased by 50% to 400%; the highest increases were recorded in regions showing damage in adults. At P10, local cerebral blood flow rates decreased by 40% to 60% in most areas, except in some forebrain regions showing no change during status epilepticus. In areas injured when status epilepticus was induced in adults, a strong hypermetabolism (Fernandes et al., 1999) not matched by comparable local cerebral blood flow increases was present in rats of all ages, whereas in damage-resistant areas, local cerebral metabolic rate for glucose and local cerebral blood flow remained coupled in the three age groups. Thus, the level of coupling between blood flow supply and metabolism is not involved in seizure-related brain damage in the developing brain, which appears to be resistant to the consequences of such a mismatch.


Assuntos
Envelhecimento/fisiologia , Animais Recém-Nascidos/fisiologia , Circulação Cerebrovascular , Convulsões/fisiopatologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Sinergismo Farmacológico , Feminino , Glucose/metabolismo , Lítio , Masculino , Neurônios/patologia , Pilocarpina , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/patologia , Convulsões/psicologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia
16.
Neuropharmacology ; 61(1-2): 313-28, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21539848

RESUMO

Lithium-pilocarpine, a relevant model of temporal lobe epilepsy was used to test the neuroprotective and antiepileptogenic effects of carisbamate. Status epilepticus (SE) was induced in adult rats by lithium and pilocarpine. Carisbamate (30, 60, 90, and 120 mg/kg) was injected at 1 and 9 h after SE onset and continued twice daily for 6 additional days. The reference groups received diazepam instead of carisbamate. Neuroprotection was assessed during the first 24 h of SE with Fluoro-Jade B and after 14 days with thionine staining. SE severity and epileptic outcome were assessed by video, and surface and depth electroencephalographic recordings. At the two highest doses, carisbamate treatment reduced SE severity; produced strong neuroprotection of hippocampus, ventral cortices, thalamus, and amygdala; prevented mossy fiber sprouting in the dentate gyrus of the hippocampus; and delayed or suppressed the occurrence of spontaneous motor seizures. Rats with no spontaneous motor seizures displayed spike-and-wave discharges that share all the characteristics of absence seizures. In conclusion, carisbamate is able to induce strong neuroprotection and affect the nature of epileptogenic events occurring during and after lithium-pilocarpine status epilepticus, reflecting marked insult- and disease-modifying effects.


Assuntos
Carbamatos/uso terapêutico , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Cloreto de Lítio/toxicidade , Pilocarpina/toxicidade , Animais , Epilepsia do Lobo Temporal/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley
17.
Epilepsia ; 49(2): 320-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17941845

RESUMO

PURPOSE: Thresholds to pentylenetetrazol (PTZ) seizures were usually based only on clinical symptoms. Our purpose was to use electroclinical patterns to assess the efficacy of a ketogenic and/or calorie-restricted diet on PTZ-induced seizures. METHODS: Forty 50-day-old rats were divided in four weight-matched groups and fed controlled diets: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), and hypocalorie ketogenic (HK). After 21 days, blood glucose and beta-hydroxybutyrate levels were determined and seizures were induced by continuous infusion of PTZ. The clinical and EEG thresholds to each seizure pattern were compared between the different groups. RESULTS: The electroclinical course of PTZ-induced seizures was similar in all groups. The HK group exhibited higher thresholds than the other ones for most clinical features: absence (p = 0.003), first overt myoclonia (p = 0.028), clonic seizure (p = 0.006), and for EEG features: first spike (p = 0.036), first spike-and-wave discharge (p = 0.014), subcontinuous spike-and-wave discharges (p = 0.005). NK, HC, and NC groups were not significantly different from each other. Blood glucose and beta-hydroxybutyrate levels were not correlated with electroclinical seizure thresholds. After the clonic seizure, despite stopping PTZ infusion, a tonic seizure occurred in some animals, without significant difference regarding the diet. CONCLUSION: This approach permitted a precise study of the electroclinical course of PTZ-induced seizures. In addition to the usually studied first overt myoclonia, we clearly demonstrated the efficiency of a calorie restricted KD in elevating thresholds to most electroclinical seizure patterns. We confirmed the lack of efficiency of the KD to reduce seizure severity once the seizure has started.


Assuntos
Restrição Calórica/métodos , Eletroencefalografia/estatística & dados numéricos , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Cetose/metabolismo , Pentilenotetrazol , Ácido 3-Hidroxibutírico/sangue , Animais , Glicemia/análise , Peso Corporal/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/metabolismo , Modelos Animais de Doenças , Ingestão de Energia , Epilepsia/dietoterapia , Cetose/etiologia , Masculino , Ratos , Ratos Wistar
18.
Epilepsia ; 46(8): 1178-87, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16060926

RESUMO

PURPOSE: Measurement of local cerebral blood flow (LCBF) is routinely used to locate the areas involved in generation and spread of seizures in epilepsy patients. Because the spatial distribution and extent of ictal CBF depends on the epileptogenic network, but also on the timing of injection of tracer, we used a rat model of amygdala-kindled seizures to follow the time-dependent changes in the distribution of LCBF changes. METHODS: Rats were implanted in the left amygdala and were fully kindled. LCBF was measured by the quantitative [(14)C]iodoantipyrine autoradiographic technique bilaterally in 35 regions. The tracer was injected at 30 s before seizure induction (early ictal), simultaneous with the application of stimulation (ictal), at 60 s after stimulation (late ictal), at the end of the electrical afterdischarge (early postictal), and at 6 min after the stimulation (late postictal). RESULTS: Rates of LCBF increased over control levels during the early ictal phase ipsilaterally in medial amygdala, frontal cortex, and ventromedian thalamus and bilaterally in the whole hippocampus, thalamic nuclei, and basal ganglia. During the ictal phase, all regions underwent hyperperfusion (81-416% increases). By 60 s after stimulation, rates of LCBF returned to control levels in most brain areas, despite ongoing seizure activity. At later times, localized foci of hypoperfusion were observed in hippocampus bilaterally, with a slight predominance in CA1 on the side of origin of the seizures. CONCLUSION: This study shows a rapid spread of activation from the stimulated amygdala bilaterally to numerous limbic, cortical, and subcortical structures. The largest hyperperfusion was recorded during the ictal period with tracer injections simultaneous with the stimulation. The unilateral site of origin of seizures led to minor asymmetrical and lateralized findings, merely at early ictal and late postictal times, whereas intermediate tracer injections induced bilateral changes. Only late postictal measurements allowed the identification of significant changes in focal structures: the hippocampus is known to play a critical role in the spread of limbic seizures.


Assuntos
Tonsila do Cerebelo/fisiologia , Mapeamento Encefálico/métodos , Encéfalo/irrigação sanguínea , Excitação Neurológica/fisiologia , Convulsões/fisiopatologia , Tonsila do Cerebelo/irrigação sanguínea , Animais , Antipirina/análogos & derivados , Autorradiografia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Radioisótopos de Carbono , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Estimulação Elétrica , Lateralidade Funcional/fisiologia , Hipocampo/irrigação sanguínea , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Sistema Límbico/irrigação sanguínea , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatologia , Masculino , Mesencéfalo/irrigação sanguínea , Mesencéfalo/metabolismo , Mesencéfalo/fisiopatologia , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional , Convulsões/diagnóstico , Fatores de Tempo , Distribuição Tecidual
19.
Epilepsia ; 44(4): 529-35, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12681001

RESUMO

PURPOSE: Acute caffeine exposure has proconvulsant effects and worsens epileptic and ischemic neuronal damage. Surprisingly, prolonged caffeine exposure decreases the susceptibility to seizures and the extent of ischemic damage. We explored whether the exposure to a low long-term dose of caffeine could protect the brain from neuronal damage and epileptogenesis in the lithium-pilocarpine model of temporal lobe epilepsy. METHODS: Rats received either plain tap water or water containing caffeine (0.3 g/L) for 15 days before the induction of status epilepticus (SE) by lithium-pilocarpine and for 7 days after SE. The extent of neuronal damage was assessed in the hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from animals killed 7 days after SE. The latency to spontaneous recurrent seizures was controlled by video monitoring. RESULTS: Caffeine treatment induced a marked, almost total neuroprotection in CA1 and a very limited protection in the hilus of the dentate gyrus, whereas damage in layers III-IV of the piriform cortex was slightly worsened by the treatment. All rats, whether they received caffeine or plain tap water, became epileptic after the same latency (17-19 days). CONCLUSIONS: Thus these data extend the neuroprotective effects of low long-term caffeine exposure to epileptic damage and confirm that the sole protection of the Ammon's horn has no influence on the genesis of spontaneous recurrent seizures in this model.


Assuntos
Anticonvulsivantes/farmacologia , Cafeína/farmacologia , Fármacos Neuroprotetores/farmacologia , Estado Epiléptico/fisiopatologia , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Convulsivantes/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/fisiologia , Cloreto de Lítio/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/patologia , Fibras Musgosas Hipocampais/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Orientação/efeitos dos fármacos , Orientação/fisiologia , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia
20.
Epilepsia ; 44(7): 893-903, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12823571

RESUMO

PURPOSE: To determine whether a pharmacologic treatment could delay or prevent the epileptogenesis induced by status epilepticus (SE) through the protection of some brain areas, we studied the effects of the long-term exposure to pregabalin (PGB) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. METHODS: SE was induced in adult and 21-day-old (P21) rats. At 20 min after pilocarpine, rats received 50 mg/kg PGB (pilo-preg) or saline (pilo-saline). PGB treatment was given daily at the dose of 50 mg/kg for 7 days after SE and at 10 mg/kg from day 8 until killing. Neuronal damage was assessed in hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from adult and P21 animals killed 6 days after SE. The number of glial fibrillary acidic protein (GFAP)-reactive astrocytes was tested by immunohistochemistry in sections adjacent to those used for cell counting. The latency to spontaneous seizures was controlled by visual observation and EEG recording. RESULTS: PGB induced neuroprotection in layer II of piriform cortex and layers III-IV of ventral entorhinal cortex of adult rats, whereas no hippocampal region was protected. In P21 rats, damage was limited to the hilus and similar in pilo-preg and pilo-saline animals. The number of GFAP-positive astrocytes was higher in pilocarpine- than in saline-treated rats. It was decreased in pilo-preg compared with pilo-saline rats in layer II of the piriform cortex. Adult pilo-preg rats became epileptic after a longer latency (39 days) than did pilo-saline rats (22 days). CONCLUSIONS: These data underline the antiepileptogenic consequences of long-term PGB treatment, possibly mediated by the protection of piriform and entorhinal cortices in the lithium-pilocarpine model of epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Epilepsia do Lobo Temporal/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Estado Epiléptico/fisiopatologia , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Convulsivantes , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/patologia , Córtex Entorrinal/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Técnicas Imunoenzimáticas , Lítio , Giro Para-Hipocampal/efeitos dos fármacos , Giro Para-Hipocampal/patologia , Giro Para-Hipocampal/fisiopatologia , Pilocarpina , Pregabalina , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia
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