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1.
Magn Reson Med ; 64(4): 1191-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20725933

RESUMO

Simultaneous electrophysiological and functional magnetic resonance imaging measurements of animal models of epilepsy are methodologically challenging, but essential to better understand abnormal brain activity and hemodynamics during seizures. In this study, functional magnetic resonance imaging of medetomidine-sedated rats was performed using novel rapid acquisition by sequential excitation and refocusing (RASER) fast imaging pulse sequence and simultaneous local field potential measurements during kainic acid-induced seizures. The image distortion caused by the hippocampal-measuring electrode was clearly seen in echo planar imaging images, whereas no artifact was seen in RASER images. Robust blood oxygenation level-dependent responses were observed in the hippocampus during kainic acid-induced seizures. The recurrent epileptic seizures were detected in the local field potential signal after kainic acid injection. The presented combination of deep electrode local field potential measurements and functional magnetic resonance imaging under medetomidine anesthesia, which does not significantly suppress kainic acid-induced seizures, provides a unique tool for studying abnormal brain activity in rats.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiopatologia , Eletrocardiografia/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Convulsões/fisiopatologia , Processamento de Sinais Assistido por Computador , Animais , Encéfalo/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Medetomidina/administração & dosagem , Ratos , Ratos Wistar
2.
Brain ; 131(Pt 6): 1506-15, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18477594

RESUMO

Temporal lobe epilepsy remains amongst the most common and drug refractory of neurological disorders. Gene therapy may provide a realistic therapeutic approach alternative to surgery for intractable focal epilepsies. To test this hypothesis, we applied here a gene therapy approach, using a recombinant adeno-associated viral (rAAV) vector expressing the human neuropeptide Y (NPY) gene, to a progressive and spontaneous seizure model of temporal lobe epilepsy induced by electrical stimulation of the temporal pole of the hippocampus, which replicates many features of the human condition. rAAV-NPY or a control vector lacking the expression cassette (rAAV-Empty) was delivered into the epileptic rat hippocampi at an early progressive stage of the disease. Chronic epileptic rats were video-EEG monitored to establish pre-injection baseline recordings of spontaneous seizures and the effect of rAAV-NPY versus rAAV-Empty vector injection. Both non-injected stimulated controls and rAAV-empty injected rats showed a similar progressive increase of spontaneous seizure frequency consistent with epileptogenesis. The delivery of rAAV-NPY in epileptic rat brain leads to a remarkable decrease in the progression of seizures as compared to both control groups and this effect was correlated with the NPY over-expression in the hippocampus. Moreover, spontaneous seizure frequency was significantly reduced in 40% of treated animals as compared to their pre-injection baseline. Our data show that this gene therapy strategy decreases spontaneous seizures and suppresses their progression in chronic epileptic rats, thus representing a promising new therapeutic strategy.


Assuntos
Epilepsia do Lobo Temporal/terapia , Terapia Genética/métodos , Neuropeptídeo Y/genética , Animais , Doença Crônica , Dependovirus/genética , Eletroencefalografia , Epilepsia do Lobo Temporal/metabolismo , Expressão Gênica , Engenharia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Hipocampo/química , Hipocampo/metabolismo , Injeções , Masculino , Neurônios/química , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução Genética/métodos , Gravação em Vídeo
3.
Peptides ; 28(2): 377-83, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17196301

RESUMO

Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory and excitatory transmission in epilepsy. Transduction of neuropeptide genes such as galanin and neuropeptide Y (NPY) in specific brain areas in experimental models of seizures resulted in significant anticonvulsant effects. In particular, the long-lasting NPY over-expression obtained in the rat hippocampus using intracerebral application of recombinant adeno-associated viral (AAV) vectors reduced the generalization of seizures from their site of onset, delayed acquisition of fully kindled seizures and afforded neuroprotection. These results establish a proof-of-principle for the applicability of AAV-NPY vectors for the inhibition of seizures in epilepsy. Additional investigations are required to demonstrate a therapeutic role of gene therapy in chronic models of seizures and to address in more detail safety concerns and possible side-effects.


Assuntos
Epilepsia/tratamento farmacológico , Terapia Genética , Neuropeptídeo Y/genética , Humanos
4.
Epilepsy Res ; 73(2): 181-91, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17161937

RESUMO

The present study investigated whether spontaneously seizing animals are a valid model for evaluating antiepileptic compounds in the treatment of human epilepsy. We examined whether clinically effective antiepileptic drugs (AEDs), including carbamazepine (CBZ), valproic acid (VPA), ethosuximide (ESM), lamotrigine (LTG), or vigabatrin (VGB) suppress spontaneous seizures in a rat model of human temporal lobe epilepsy, in which epilepsy is triggered by status epilepticus induced by electrical stimulation of the amygdala. Eight adult male rats with newly diagnosed epilepsy and focal onset seizures were included in the study. Baseline seizure frequency was determined by continuous video-electroencephalography (EEG) monitoring during a 7 days baseline period. This was followed by a 2-3 days titration period, a 5-7 days treatment period, and a 2-3 days wash-out period. During the 5-7 days treatment period, animals were treated successively with CBZ (120 mg/kg/day), VPA (600 mg/kg/day), ESM (400 mg/kg/day), LTG (20 mg/kg/day), and VGB (250 mg/kg/day). VPA, LTG, and VGB were the most efficient of the compounds investigated, decreasing the mean seizure frequency by 83, 84, and 60%, respectively. In the VPA group, the percentage of rats with a greater than 50% decrease in seizure frequency was 100%, in the LTG group 88%, in the VGB group 83%, in the CBZ group 29%, and in the ESM group 38%. During the 7 day treatment period, 20% of the VPA-treated animals and 14% of the CBZ-treated animals became seizure-free. These findings indicate that rats with focal onset spontaneous seizures respond to the same AEDs as patients with focal onset seizures. Like in humans, the response to AEDs can vary substantially between animals. These observations support the idea that spontaneously seizing animals are a useful tool for testing novel compounds for the treatment of human epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Tonsila do Cerebelo/patologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Eletroencefalografia , Epilepsia do Lobo Temporal/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/etiologia , Gravação em Vídeo
5.
Epilepsy Res ; 74(1): 45-54, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17289347

RESUMO

The current first line treatment of status epilepticus (SE) is based on the use of compounds that enhance GABAergic transmission or block sodium channels. These treatments discontinue SE in only two-thirds of patients, and therefore new therapeutic approaches are needed. We investigated whether a novel water-soluble AMPA antagonist, NS1209, discontinues SE in adult rats. SE was induced by electrical stimulation of the amygdala or subcutaneous administration of kainic acid. Animals were monitored continuously with video-electroencephalography during SE and drug treatment. We found that NS1209 could be safely administered to rats undergoing electrically induced SE at doses up to 50mg/kg followed by intravenous infusion of 5mg/kg for up to 24h. NS1209 administered as a bolus dose of 10-50mg/kg (i.p. or i.v.) followed by infusion of 4 or 5mg/kg h (i.v.) for 2-24h effectively discontinued electrically induced SE in all animals within 30-60 min, and there was no recurrence of SE after a 24-h infusion. Kainate-induced SE was similarly blocked by 10 or 30 mg/kg NS1209 (i.v.). To compare the efficacy and neuroprotective effects of NS1209 with those of diazepam (DZP), one group of rats received DZP (20mg/kg, i.p. and another dose of 10 mg/kg 6h later). By using the administration protocols described, the anticonvulsant effect of NS1209 was faster and more complete than that of DZP. NS1209 treatment (20 mg/kg bolus followed by 5mg/kg h infusion for 24 h) was neuroprotective against SE-induced hippocampal neurodegeneration, but to a lesser extent than DZP. These findings suggest that AMPA receptor blockade by NS1209 provides a novel and mechanistically complimentary addition to the armamentarium of drugs used to treat SE in humans.


Assuntos
Anticonvulsivantes/administração & dosagem , Hipocampo/efeitos dos fármacos , Pirróis/administração & dosagem , Receptores de AMPA/antagonistas & inibidores , Estado Epiléptico/tratamento farmacológico , Tetra-Hidroisoquinolinas/administração & dosagem , Tonsila do Cerebelo/patologia , Animais , Anticonvulsivantes/farmacologia , Diazepam/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimulação Elétrica/efeitos adversos , Eletroencefalografia , Ácido Caínico , Masculino , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/etiologia , Tetra-Hidroisoquinolinas/farmacologia , Gravação em Vídeo
6.
J Neurotrauma ; 34(7): 1482-1487, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27707084

RESUMO

Sleep disturbances commonly occur after traumatic brain injury (TBI) and may predispose patients to epileptic seizures. We hypothesized that unprovoked seizure occurrence post-TBI depends on the sleep-wake cycle, and that the electrographic characteristics of a given sleep stage provide biomarkers for post-traumatic epilepsy (PTE). We show, in a rat lateral fluid percussion model, that 92% of spontaneous generalized seizures occur during the transition from stage III to rapid eye movement sleep. Moreover, a reduction in spindle duration and dominant frequency during the transition stage present as specific and sensitive noninvasive biomarkers for experimentally induced PTE with generalized electrographic seizures.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Epilepsia Pós-Traumática/fisiopatologia , Fases do Sono/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Animais , Lesões Encefálicas Traumáticas/complicações , Modelos Animais de Doenças , Epilepsia Pós-Traumática/etiologia , Masculino , Ratos , Ratos Sprague-Dawley , Transtornos do Sono-Vigília/etiologia , Sono REM/fisiologia
7.
Epilepsy Res ; 136: 18-34, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28753497

RESUMO

Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α2-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α2-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α2A-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α2C-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Pós-Traumática/tratamento farmacológico , Imidazóis/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Avaliação Pré-Clínica de Medicamentos , Epilepsia Pós-Traumática/fisiopatologia , Epilepsia Pós-Traumática/psicologia , Masculino , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Estudo de Prova de Conceito , Pirazóis/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Rimonabanto , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Memória Espacial/efeitos dos fármacos
8.
Epilepsy Res ; 72(1): 25-38, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16911865

RESUMO

The aim was to test the hypothesis that occlusion of the middle cerebral artery (MCA) results in the development of epilepsy in rats. Further, we investigated whether lesion volume, hippocampal pathology, early seizures, or severity of behavioral impairment is associated with the development and severity of epilepsy or interictal spiking. MCA occlusion was induced by intracerebral injection of endothelin-1 (ET; 120 pmol). One group of ET-injected rats were followed-up for 6 months (n = 15) and another for 12 months (n = 20). Sham-operated animals were injected with saline (n = 12). Occurrence of early and late seizures was monitored by intermittent video-electroencephalography. Sensorimotor function was tested with the running wheel and tapered beam-walking tests. Emotional learning and memory were assessed with the fear conditioning test and spatial learning and memory with the Morris water maze. Finally, brains were processed for histology. Only one rat developed late spontaneous seizures (i.e., epilepsy). Epileptiform interictal spiking was detected in 9 of 26 animals. Early seizures did not predict the development of epilepsy, spiking activity, or severity of behavioral impairment. Production of MCA stroke by intracerebral injection of ET was not a strong trigger of epileptogenesis in adult rats. Further studies are needed to investigate the effect of age, genetic background, and location of ET-injection on the development of hyperexcitability and the risk of post-stroke epileptogenesis.


Assuntos
Transtornos Cerebrovasculares/complicações , Epilepsia/etiologia , Hipocampo/patologia , Convulsões/etiologia , Animais , Comportamento Animal , Transtornos Cerebrovasculares/induzido quimicamente , Condicionamento Psicológico/fisiologia , Eletrodos Implantados , Eletroencefalografia , Endotelina-1 , Seguimentos , Masculino , Aprendizagem em Labirinto/fisiologia , Artéria Cerebral Média/patologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Gravação em Vídeo
9.
Epilepsy Res ; 63(1): 27-42, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15716080

RESUMO

Prevention of epileptogenesis after brain insults, such as status epilepticus (SE), head trauma, or stroke, remains a challenge. Even if epilepsy cannot be prevented, it would be beneficial if the pathologic process could be modified to result in a less severe disease. We examined whether early discontinuation of SE reduces the risk of epilepsy or results in milder disease. Epileptogenesis was triggered with SE induced by electrical stimulation of the amygdala. Animals (n = 72) were treated with vehicle or diazepam (DZP, 20 mg/kg) 2 h or 3 h after the beginning of SE. Electrode-implanted non-stimulated rats served as controls for histology. All animals underwent continuous long-term video-electroencephalography monitoring 7-9 weeks and 11-15 weeks later to detect the occurrence and severity of spontaneous seizures. As another outcome measure, the severity of hippocampal damage was assessed in histologic sections. In the vehicle group, 94% of animals developed epilepsy. DZP treatment reduced the percentage of epileptic animals to 42% in the 2-h DZP group and to 71% in the 3-h DZP group (p < 0.001 and p < 0.05 compared to the vehicle group, respectively). If epilepsy developed, the seizures were less frequent in DZP-treated animals compared to the vehicle group (median 16.4 seizures/day), particularly in the 2-h DZP group (median 0.4 seizures/day). Finally, if DZP treatment was started 2 h, but not 3 h after SE, the severity of hippocampal cell loss was milder and the density of mossy-fiber sprouting was lower than in the vehicle group. These data indicate that treatment of SE with DZP within 2 h reduces the risk of epilepsy later in life, and if epilepsy develops, it is milder.


Assuntos
Anticonvulsivantes/administração & dosagem , Diazepam/administração & dosagem , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Tonsila do Cerebelo/efeitos da radiação , Animais , Comportamento Animal , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Estimulação Elétrica/efeitos adversos , Eletroencefalografia/métodos , Seguimentos , Hipocampo/patologia , Masculino , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/patologia , Fibras Musgosas Hipocampais/efeitos da radiação , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Convulsões/etiologia , Estado Epiléptico/etiologia , Estado Epiléptico/mortalidade , Fatores de Tempo , Gravação de Videoteipe/métodos
10.
Comput Methods Programs Biomed ; 79(2): 151-9, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16005102

RESUMO

This study concerns the detection of epileptic seizures from electroencephalogram (EEG) data using computational methods. Using short sliding time windows, a set of features is computed from the data. The feature set includes time domain, frequency domain and nonlinear features. Discriminant analysis is used to determine the best seizure-detecting features among them. The findings suggest that the best results can be achieved by using a combination of features from the linear and nonlinear realms alike.


Assuntos
Convulsões/fisiopatologia , Algoritmos , Análise Discriminante , Eletroencefalografia , Fractais , Humanos , Dinâmica não Linear
11.
Prog Brain Res ; 135: 67-83, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12143371

RESUMO

The present study was designed to address the question of whether recurrent spontaneous seizures cause progressive neuronal damage in the brain. Epileptogenesis was triggered by status epilepticus (SE) induced by electrically stimulating the amygdala in rat. Spontaneous seizures were continuously monitored by video-EEG for up to 6 months. The progression of damage in individual rats was assessed with serial magnetic resonance imaging (MRI) by quantifying the markers of neuronal damage (T2, T1 rho, and Dav) in the amygdala and hippocampus. The data indicate that SE induces structural alterations in the amygdala and the septal hippocampus that progressively increased for approximately 3 weeks after SE. T2, T1 rho, and Dav did not normalize during the 50 days of follow-up after SE, suggesting ongoing neuronal death due to spontaneous seizures. Consistent with these observations, Fluoro-Jade B-stained preparations revealed damaged neurons in the hippocampus of spontaneously seizing animals that were sacrificed up to 62 days after SE. The presence of Fluoro-Jade B-positive neurons did not, however, correlate with the number of spontaneous seizures, but rather with the time interval from SE to perfusion. Further, there were no Fluoro-Jade B-positive neurons in frequently seizing rats that were perfused for histology 6 months after SE. Also, the number of lifetime seizures did not correlate with the severity of neuronal loss in the hilus of the dentate gyrus assessed by stereologic cell counting. The methodology used in the present experiments did not demonstrate a clear association between the number or occurrence of spontaneous seizures and the severity of hilar cell death. The ongoing hippocampal damage in these epileptic animals detected even 2 month after SE was associated with epileptogenic insult, that is, SE rather than spontaneous seizures.


Assuntos
Tonsila do Cerebelo/patologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Neurônios/patologia , Estado Epiléptico/patologia , Animais , Modelos Animais de Doenças , Estimulação Elétrica , Eletroencefalografia , Imageamento por Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Convulsões/patologia , Fatores de Tempo
12.
Neurosci Lett ; 349(1): 58-62, 2003 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-12946586

RESUMO

Changes in the structure and function of inhibitory GABA(A) receptors may contribute to epileptogenesis. We have used the in situ hybridization technique to study GABA(A) receptor alpha2, alpha4, beta3 and gamma2 subunit mRNA expression in the hippocampus of spontaneously seizing rats with chronic temporal lobe epilepsy. In control rats, all four subunit mRNAs were expressed in the hippocampal subregions but the intensity of expression varied significantly between the subfields. In epileptic rats, alpha2 expression was decreased in CA3c, and alpha4 in CA1, but beta3 was increased in all subregions, in particular in the granule cell layer. Our results suggest that GABA(A) receptor undergoes region selective subunit changes during epileptogenesis in the hippocampus of rats with chronic temporal lobe epilepsy.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , Epilepsia/metabolismo , Hipocampo/metabolismo , Subunidades Proteicas/genética , Receptores de GABA-A/genética , Animais , Doença Crônica , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/fisiopatologia , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/fisiopatologia , Predisposição Genética para Doença/genética , Hipocampo/fisiopatologia , Masculino , Inibição Neural/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/metabolismo
13.
Epilepsy Res ; 58(2-3): 119-32, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15120743

RESUMO

Prevention of epileptogenesis in patients with acute brain damaging insults like status epilepticus (SE) is a major challenge. We investigated whether lamotrigine (LTG) treatment started during SE is antiepileptogenic or disease-modifying. To mimic a clinical study design, LTG treatment (20 mg/kg) was started 2 h after the beginning of electrically induced SE in 14 rats and continued for 11 weeks (20 mg/kg per day for 2 weeks followed by 10 mg/kg per day for 9 weeks). One group of rats (n = 14) was treated with vehicle. Nine non-stimulated rats with vehicle treatment served as controls. Outcome measures were occurrence of epilepsy, severity of epilepsy, and histology (neuronal loss, mossy fiber sprouting). Clinical occurrence of seizures was assessed with 1-week continuous video-electroencephalography monitoring during the 11th (i.e. during treatment) and 14th week (i.e. after drug wash-out) after SE. LTG reduced the number of electrographic seizures during SE to 43% of that in the vehicle group (P < 0.05). In the vehicle group, 93% (13/14), and in the LTG group, 100% (14/14) of the animals, developed epilepsy. In both groups, 64% of the rats had severe epilepsy (seizure frequency >1 per day). The mean frequency of spontaneous seizures, seizure duration, or behavioral severity of seizures did not differ between groups. The severity of hippocampal neuronal damage and density of mossy fiber sprouting were similar. In LTG-treated rats with severe epilepsy, however, the duration of seizures was shorter (34 versus 54s, P < 0.05) and the behavioral seizure score was milder (1.4 versus 3.4, P < 0.05) during LTG treatment than after drug wash-out. LTG treatment started during SE and continued for 11 weeks was not antiepileptogenic but did not worsen the outcome. These data, together with earlier studies of other antiepileptic drugs, suggest that strategies other than Na(+)-channel blockade should be explored to modulate the molecular cascades leading to epileptogenesis after SE.


Assuntos
Epilepsia/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Esquema de Medicação , Estimulação Elétrica/métodos , Epilepsia/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Lamotrigina , Masculino , Ratos , Ratos Sprague-Dawley , Triazinas/farmacologia
14.
Epilepsy Res ; 61(1-3): 119-40, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15451014

RESUMO

Stimulation of alpha(2)-adrenoceptors delays the development of kindling, a model of epileptogenesis in humans. Blocking alpha(2)-adrenoceptors is proconvulsant, but has beneficial effects on somatomotor recovery after experimental stroke. We investigated whether atipamezole, a selective alpha(2)-adrenoceptor antagonist, affects the recovery process from status epilepticus (SE)-induced brain damage, which affects the risk of epileptogenesis. Vehicle or atipamezole (100 microg/kg/h) treatment was started 1 week after the induction of SE and continued for 9 weeks using Alzet minipumps (n = 70). Development and severity of epilepsy, spatial and emotional learning, and histologic analysis were used as outcome measures. There were no differences in the percentage of animals with epilepsy in the different treatment groups. In the atipamezole group, however, daily seizure frequency was lower (P < 0.01), a higher percentage of epileptic animals had mild epilepsy (<1 seizure/day; P < 0.01), and seizure frequency did not increase over time compared with the vehicle group. The atipamezole group had milder hilar cell damage (P < 0.05) and less intense mossy fiber sprouting (P < 0.05). Behavioral impairments were similar between groups. Our data indicate that chronic treatment with atipamezole does not prevent epileptogenesis. There is, however, a disease-modifying effect; that is, the epilepsy that develops is milder and non-progressive. These data warrant further studies.


Assuntos
Agonistas alfa-Adrenérgicos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/prevenção & controle , Imidazóis/uso terapêutico , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/farmacocinética , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Comportamento Animal/fisiologia , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Progressão da Doença , Estimulação Elétrica , Eletrodos Implantados , Eletroencefalografia , Eletrofisiologia , Emoções/efeitos dos fármacos , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/psicologia , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Bombas de Infusão Implantáveis , Excitação Neurológica/efeitos dos fármacos , Excitação Neurológica/fisiologia , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/patologia , Estado Epiléptico/prevenção & controle
15.
Epilepsy Res ; 54(1): 1-10, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12742590

RESUMO

Post-stroke seizures occur in 5-20% of patients. Modeling of stroke-induced seizures in animals provides a useful tool for investigating the molecular basis of epileptogenesis and for developing therapies for stroke patients at increased risk for epileptogenesis. The questions addressed in the study were: (1) Do rats develop spontaneous seizures after transient occlusion of the middle cerebral artery (MCAO)? (2) Is epileptogenesis associated with impaired hippocampus-dependent spatial learning and memory? (3) Are the functional abnormalities linked to axonal plasticity in the dentate gyrus? (4) Does the sensorimotor impairment induced by MCAO predict the risk of epileptogenesis? Adult male Sprague-Dawley rats were subjected to MCAO for 120 min. Development of spontaneous seizures was monitored by 1 week of continuous video-electroencephalographic (EEG) recordings at 3, 7, and 12 months after MCAO. Spontaneous seizures were not detected during 1-year follow-up in ischemic rats. Animals were, however, impaired in the spatial memory task (P<0.001), which was not associated with altered hippocampal LTP or abnormal mossy fiber sprouting (Timm staining). Animals also had a long-lasting sensorimotor deficit (P<0.05). The present study indicates that MCAO causes long-lasting sensorimotor and spatial memory impairment, but does not induce epileptogenesis or spontaneous seizures.


Assuntos
Isquemia Encefálica/complicações , Epilepsia/etiologia , Transtornos da Memória/etiologia , Artéria Cerebral Média/fisiologia , Transtornos dos Movimentos/etiologia , Distúrbios Somatossensoriais/etiologia , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Eletrodos Implantados , Eletroencefalografia , Hipocampo/patologia , Hipocampo/fisiopatologia , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/fisiopatologia , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/psicologia , Fibras Musgosas Hipocampais/patologia , Transtornos dos Movimentos/psicologia , Plasticidade Neuronal/fisiologia , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Distúrbios Somatossensoriais/psicologia
16.
J Neurotrauma ; 30(7): 546-56, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23259713

RESUMO

The present study was designed to test a hypothesis that functional magnetic resonance imaging (fMRI) can be used to monitor functional impairment and recovery after moderate experimental traumatic brain injury (TBI). Moderate TBI was induced by lateral fluid percussion injury in adult rats. The severity of brain damage and functional recovery in the primary somatosensory cortex (S1) was monitored for up to 56 days using fMRI, cerebral blood flow (CBF) by arterial spin labeling, local field potential measurements (LFP), behavioral assessment, and histology. All the rats had reduced blood-oxygen-level-dependent (BOLD) responses during the 1st week after trauma in the ipsilateral S1. Forty percent of these animals showed recovery of the BOLD response during the 56 day follow-up. Unexpectedly, no association was found between the recovery in BOLD response and the volume of the cortical lesion or thalamic neurodegeneration. Instead, the functional recovery occurred in rats with preserved myelinated fibers in layer VI of S1. This is, to our knowledge, the first study demonstrating that fMRI can be used to monitor post-TBI functional impairment and consequent spontaneous recovery. Moreover, the BOLD response was associated with the density of myelinated fibers in the S1, rather than with neurodegeneration. The present findings encourage exploration of the usefulness of fMRI as a noninvasive prognostic biomarker for human post-TBI outcomes and therapy responses.


Assuntos
Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Imageamento por Ressonância Magnética , Recuperação de Função Fisiológica , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
17.
Epilepsy Res ; 94(1-2): 75-85, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21300523

RESUMO

Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored.


Assuntos
Anticonvulsivantes/uso terapêutico , Encéfalo/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Canais de Sódio/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/mortalidade , Precursor de Proteína beta-Amiloide/genética , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Epilepsia/etiologia , Epilepsia/mortalidade , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Transgênicos , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Análise Espectral , Gravação em Vídeo/métodos
18.
Exp Neurol ; 205(2): 501-5, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17442304

RESUMO

Pilocarpine administration to rats results in status epilepticus (SE) and after a latency period to the occurrence of spontaneous seizures. The model is commonly used to investigate mechanisms of epileptogenesis as well as the antiepileptic effects of novel compounds. Surprisingly, there have been no video-EEG studies determining the duration of latency period from SE to the appearance of the first spontaneous seizures or the type and frequency of spontaneous seizures at early phase of pilocarpine-induced epilepsy even though such information is critical for design of such studies. To address these questions, we induced SE with pilocarpine in 29 adult male Wistar rats with cortical electrodes. Rats were continuously video-EEG monitored during SE and up to 23 days thereafter. The first spontaneous seizures occurred 7.2+/-3.6 days after SE. During the follow-up, the mean daily seizure frequency was 2.6+/-1.9, the mean seizure duration 47+/-7 s, and the mean behavioral seizure score 3.2+/-0.9. Typically first seizures were partial (score 1-2). Interestingly, spontaneous seizures occurred in clusters with cyclicity, peaking every 5 to 8 days. These data show that in the pilocarpine model of temporal lobe epilepsy the latency period is short. Because many of the early seizures are partial and the seizures occur in clusters, the true phenotype of epilepsy triggered by pilocarpine-induced SE may be difficult to characterize without continuous long-term video-EEG monitoring. Finally, our data suggest that the model can be used for studies aiming at identifying the mechanisms of seizure clustering.


Assuntos
Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/fisiopatologia , Agonistas Muscarínicos , Pilocarpina , Convulsões/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Eletroencefalografia , Masculino , Ratos , Ratos Wistar , Recidiva , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia , Estado Epiléptico/psicologia
19.
Epilepsia ; 48 Suppl 2: 13-20, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17571349

RESUMO

Epileptogenesis refers to a phenomenon in which the brain undergoes molecular and cellular alterations after a brain-damaging insult, which increase its excitability and eventually lead to the occurrence of recurrent spontaneous seizures. Common epileptogenic factors include traumatic brain injury (TBI), stroke, and cerebral infections. Only a subpopulation of patients with any of these brain insults, however, will develop epilepsy. Thus, there are two great challenges: (1) identifying patients at risk, and (2) preventing and/or modifying the epileptogenic process. Target identification for antiepileptogenic treatments is difficult in humans because patients undergoing epileptogenesis cannot currently be identified. Animal models of epileptogenesis are therefore necessary for scientific progress. Recent advances in the development of experimental models of epileptogenesis have provided tools to investigate the molecular and cellular alterations and their temporal appearance, as well as the epilepsy phenotype after various clinically relevant epileptogenic etiologies, including TBI and stroke. Studying these models will lead to answers to critical questions such as: Do the molecular mechanisms of epileptogenesis depend on the etiology? Is the spectrum of network alterations during epileptogenesis the same after various clinically relevant etiologies? Is the temporal progression of epileptogenesis similar? Work is ongoing, and answers to these questions will facilitate the identification of molecular targets for antiepileptogenic treatments, the design of treatment paradigms, and the determination of whether data from one etiology can be extrapolated to another.


Assuntos
Modelos Animais de Doenças , Epilepsia/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Eletroencefalografia/estatística & dados numéricos , Epilepsia/genética , Epilepsia/patologia , Previsões , Expressão Gênica , Humanos , Canais Iônicos/fisiologia , Biologia Molecular , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Fenótipo , Ratos , Projetos de Pesquisa/tendências , Convulsões/genética , Convulsões/patologia , Convulsões/fisiopatologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Gravação de Videoteipe
20.
Epilepsia ; 47(5): 820-9, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16686646

RESUMO

PURPOSE: The lateral nucleus of the amygdala is critical for fear conditioning, a paradigm of emotional learning, which requires recognition of an unconditioned stimulus as aversive and association of conditioned stimuli with an unconditioned stimulus. Some patients with temporal lobe epilepsy have amygdaloid damage associated with impaired emotional learning. Fear conditioning also is impaired at least in some animal models of epilepsy. We studied whether contextual or tone-cued fear conditioning is impaired in two status epilepticus models of epilepsy and whether impairment correlates with the extent of damage in the lateral nucleus of the amygdala. METHODS: We induced epilepsy in rats by either systemic kainic acid administration or electrical amygdala stimulation. Behavioral reactions in all phases of fear conditioning were analyzed from videotapes. Damage to the lateral nucleus of the amygdala was analyzed from thionin-stained sections both histologically and by volumetry. RESULTS: Immediate reflexive responses to unconditioned and conditioned stimuli were preserved, whereas the freezing response to an unconditioned stimulus was reduced. Contextual conditioning was severely impaired, whereas tone-cued conditioning was better preserved. The lateral nucleus pathology did not correlate with impaired fear conditioning. CONCLUSIONS: These data suggest that processing of complex contextual stimuli is severely affected in experimental epilepsy, whereas conditioning to simple cues is better preserved.


Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Epilepsia/induzido quimicamente , Epilepsia/etiologia , Medo/fisiologia , Ácido Caínico , Estimulação Acústica , Animais , Comportamento Animal/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Estimulação Elétrica , Epilepsia/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/fisiopatologia , Reação de Congelamento Cataléptica/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/etiologia , Estado Epiléptico/fisiopatologia , Gravação de Videoteipe
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