RESUMO
OBJECTIVE: Epilepsy is the most common neurological chronic condition worldwide, affecting about 2% of world population. Temporal lobe epilepsy (TLE) reaches 40% of all cases of this condition, and it is highly refractory to pharmacological treatment. Physical activity has been suggested as complementary therapy for epilepsy. However, there is no consistent information whether all these effects are plenty applicable to females, since clinical and experimental studies concerning physical exercise and epilepsy are largely performed in males. Females are worthy of special attention due to gender specific particularities such as hormonal cyclical rhythm and possible pregnancy. Therefore, this study aimed to investigate the impact of two types of exercise programs (Forced and Voluntary) in female Wistar rats submitted to temporal lobe epilepsy induced by pilocarpine. METHODS: Animals were divided into four groups: Control (healthy), Epilepsy, Epilepsy/Forced (exercise in a treadmill) and Epilepsy/Voluntary (free access to wheel). Behavioral and histological analyses were evaluated among groups. RESULTS: Voluntary exercise was able to reduce seizure frequency and anovulatory estrous cycle occurrence. Yet, both types of exercise attenuated the mossy fiber sprouting in dentate gyrus. CONCLUSION: Our results indicate that voluntary exercise exerts a positive effect on epilepsy in female gender. Further investigations are necessary to better elucidate mechanisms involved in these responses, since these effects do not act in the same manner in male and female rats.
Assuntos
Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/reabilitação , Condicionamento Físico Animal/métodos , Análise de Variância , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Ciclo Estral , Feminino , Locomoção , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/patologia , Agonistas Muscarínicos/toxicidade , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
PURPOSE: Mossy fiber sprouting (MFS) is a frequent finding following status epilepticus (SE). The present study aimed to test the feasibility of using manganese-enhanced magnetic resonance imaging (MEMRI) to detect MFS in the chronic phase of the well-established pilocarpine (Pilo) rat model of temporal lobe epilepsy (TLE). METHODS: To modulate MFS, cycloheximide (CHX), a protein synthesis inhibitor, was coadministered with Pilo in a subgroup of animals. In vivo MEMRI was performed 3 months after induction of SE and compared to the neo-Timm histologic labeling of zinc mossy fiber terminals in the dentate gyrus (DG). KEY FINDINGS: Chronically epileptic rats displaying MFS as detected by neo-Timm histology had a hyperintense MEMRI signal in the DG, whereas chronically epileptic animals that did not display MFS had minimal MEMRI signal enhancement compared to nonepileptic control animals. A strong correlation (r = 0.81, p < 0.001) was found between MEMRI signal enhancement and MFS. SIGNIFICANCE: This study shows that MEMRI is an attractive noninvasive method for detection of mossy fiber sprouting in vivo and can be used as an evaluation tool in testing therapeutic approaches to manage chronic epilepsy.
Assuntos
Epilepsia/patologia , Hipocampo/patologia , Imageamento por Ressonância Magnética , Manganês , Fibras Musgosas Hipocampais/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Cicloeximida/administração & dosagem , Modelos Animais de Doenças , Interações Medicamentosas , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Masculino , Fibras Musgosas Hipocampais/patologia , Agonistas Muscarínicos/toxicidade , Pilocarpina/toxicidade , Inibidores da Síntese de Proteínas/administração & dosagem , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Tiopental/farmacologia , Tiopental/uso terapêuticoRESUMO
Psychiatric co-morbidities in epilepsy are common in patients with temporal lobe epilepsy (TLE). Pathological alterations in TLE are well characterised; however, neuropathologic data are relatively scale regarding the association between psychiatric diseases and epilepsy. Our objective was to evaluate the clinical data of 46 adult TLE patients with and without psychiatric co-morbidities and to correlate the data with hippocampal neuronal density and mossy fiber sprouting. Accordingly, patients were grouped as follows: TLE patients without history of psychiatric disorder (TLE, n=16), TLE patients with interictal psychosis (TLE+P, n=14), and TLE patients with major depression (TLE+D, n=16). Hippocampi from autopsies served as non-epileptic controls (n=10). TLE+P exhibited significantly diminished mossy fiber sprouting and decreased neuronal density in the entorhinal cortex when compared with TLE. TLE+P showed significantly poorer results in verbal memory tasks. TLE+D exhibited significantly increased mossy fiber sprouting length when compared with TLE and TLE+P. Further, a higher proportion of TLE+D and TLE+P presented secondarily generalised seizures than did TLE. Our results indicate that TLE patients with psychiatric disorders have distinct features when compared with TLE patients without psychiatric co-morbidities and that these changes may be involved in either the manifestation or the maintenance of psychiatric co-morbidities in epilepsy.
Assuntos
Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Transtornos Mentais/patologia , Fibras Musgosas Hipocampais/patologia , Neurônios/patologia , Adulto , Análise de Variância , Autopsia , Contagem de Células , Eletroencefalografia , Epilepsia do Lobo Temporal/epidemiologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Transtornos Mentais/cirurgia , Fibras Musgosas Hipocampais/metabolismo , Neurônios/metabolismo , Fosfopiruvato Hidratase/metabolismo , Coloração e RotulagemRESUMO
Malnutrition during the earliest stages of life may result in innumerable brain problems. Moreover, this condition could increase the chances of developing neurological diseases, such as epilepsy. We analyzed the effects of early-life malnutrition on susceptibility to epileptic seizures induced by the pilocarpine model of epilepsy. Wistar rat pups were kept on a starvation regimen from day 1 to day 21 after birth. At day 60, 16 animals (8 = well-nourished; 8 = malnourished) were exposed to the pilocarpine experimental model of epilepsy. Age-matched well-nourished (n = 8) and malnourished (n = 8) rats were used as controls. Animals were video-monitored over 9 weeks. The following behavioral parameters were evaluated: first seizure threshold (acute period of the pilocarpine model); status epilepticus (SE) latency; first spontaneous seizure latency (silent period), and spontaneous seizure frequency during the chronic phase. The cell and mossy fiber sprouting (MFS) density were evaluated in the hippocampal formation. Our results showed that the malnourished animals required a lower pilocarpine dose in order to develop SE (200 mg/kg), lower latency to reach SE, less time for the first spontaneous seizure and higher seizure frequency, when compared to well-nourished pilocarpine rats. Histopathological findings revealed a significant cell density reduction in the CA1 region and intense MFS among the malnourished animals. Our data indicate that early malnutrition greatly influences susceptibility to seizures and behavioral manifestations in adult life. These findings suggest that malnutrition in infancy reduces the threshold for epilepsy and promotes alterations in the brain that persist into adult life.
Assuntos
Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Desnutrição/complicações , Desnutrição/patologia , Animais , Animais Recém-Nascidos , Convulsivantes/toxicidade , Modelos Animais de Doenças , Humanos , Transtornos da Nutrição do Lactente/complicações , Transtornos da Nutrição do Lactente/patologia , Recém-Nascido , Fibras Musgosas Hipocampais/patologia , Pilocarpina/toxicidade , Ratos , Ratos WistarRESUMO
Intrahippocampal administration of kainic acid (KA) induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 +/- 8 min in saline controls (N = 4) which increased to 369 +/- 71 and 322 +/- 63 min in animals receiving herbimycin A (1.74 nmol, N = 4) and K252a (10 pmol, N = 4), respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A- and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90% of cell loss in KA-treated animals) in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.
Assuntos
Benzoquinonas/farmacologia , Carbazóis/farmacologia , Epilepsia do Lobo Temporal/fisiopatologia , Alcaloides Indólicos/farmacologia , Ácido Caínico/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Análise de Variância , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Eletroencefalografia , Inibidores Enzimáticos/farmacologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Sistema Límbico/citologia , Sistema Límbico/efeitos dos fármacos , Masculino , Fibras Musgosas Hipocampais/patologia , Fibras Musgosas Hipocampais/fisiopatologia , Fatores de Crescimento Neural/metabolismo , Ratos , Ratos Wistar , Rifabutina/análogos & derivados , Convulsões/fisiopatologia , Estatísticas não ParamétricasRESUMO
Intrahippocampal administration of kainic acid (KA) induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 ± 8 min in saline controls (N = 4) which increased to 369 ± 71 and 322 ± 63 min in animals receiving herbimycin A (1.74 nmol, N = 4) and K252a (10 pmol, N = 4), respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A- and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90 percent of cell loss in KA-treated animals) in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.
Assuntos
Animais , Masculino , Ratos , Benzoquinonas/farmacologia , Carbazóis/farmacologia , Epilepsia do Lobo Temporal/fisiopatologia , Alcaloides Indólicos/farmacologia , Ácido Caínico/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Análise de Variância , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Eletroencefalografia , Inibidores Enzimáticos/farmacologia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Ácido Caínico/farmacologia , Sistema Límbico/citologia , Sistema Límbico/efeitos dos fármacos , Fibras Musgosas Hipocampais/patologia , Fibras Musgosas Hipocampais/fisiopatologia , Fatores de Crescimento Neural , Ratos Wistar , Estatísticas não Paramétricas , Convulsões/fisiopatologiaRESUMO
PURPOSE: To evaluate the clinical and hippocampal histological features of patients with mesial temporal lobe epilepsy (MTLE) in both familial (FMTLE) and sporadic (SMTLE) forms. METHODS: Patients with FMTLE (n = 20) and SMTLE (n = 39) who underwent surgical treatment for refractory seizures were studied at the University of São Paulo School of Medicine at Ribeirão Preto. FMTLE was defined when at least two individuals in a family had clinical diagnosis of MTLE. Hippocampi from all patients were processed for Nissl/HE and Timm's stainings. Both groups were compared for clinical variables, hippocampal cell densities, and intensity of supragranular mossy fiber staining. RESULTS: There were no significant differences between FMTLE and SMTLE groups in the following: age at the surgery, age of first usual epileptic seizure, history of initial precipitating injury (IPI), age of IPI, latent period, ictal and interictal video-EEG patterns, presence of hippocampal atrophy and signal changes at MRI, and postoperative outcome. In addition, no differences were found in cell densities in hippocampal cornu ammonis subfields (CA1, CA2, CA3, CA4), fascia dentata, polymorphic region, subiculum, prosubiculum, and presubiculum. However, patients with SMTLE had greater intensity of mossy fiber Timm's staining in the fascia dentata-inner molecular layer (p< 0.05). DISCUSSION: Patients with intractable FMTLE present a clinical profile and most histological findings comparable to patients with SMTLE. Interestingly, mossy fiber sprouting was less pronounced in patients with FMTLE, suggesting that, when compared to SMTLE, patients with FMTLE respond differently to plastic changes plausibly induced by cell loss, neuronal deafferentation, or epileptic seizures.
Assuntos
Epilepsia do Lobo Temporal/genética , Hipocampo/patologia , Adulto , Lobectomia Temporal Anterior , Atrofia , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Seguimentos , Hipocampo/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fibras Musgosas Hipocampais/patologia , Plasticidade Neuronal/genética , Neurônios/patologia , EscleroseRESUMO
We tested in 70-day-old Sprague-Dawley rats, whether malnutrition imposed during different periods of hippocampal development produced deleterious effects on the total reference volume of the mossy fiber system. Animals were treated under four nutritional conditions: (a) well nourished; (b) prenatal protein malnourished; (c) chronic protein malnourished and (d) postnatal protein malnourished. Timm's stained material was used in coronal hippocampal sections (40 microm) to estimate--using the Principle of Cavalieri--the total reference volume of the mossy fiber system in each experimental group. Our results show that chronic and postnatal protein malnourished, but not prenatal malnourished rats, decrease the mossy fiber system and the total reference volume of the mossy fiber system are selectively vulnerable to the type of dietary restriction. Thus, chronic and posnatal protein malnutrition produce deleterious effects, but only rats under prenatal protein malnutrition were able to reorganize synapses in this plexus. These findings raise the possibility that chronic malnutrition, as a long-term stressful factor, might be an important paradigm to test structural hippocampal changes that produce physiological and pathophysiological effects, or the possibility to recover its function for nutritional rehabilitation.
Assuntos
Transtornos da Nutrição Fetal/patologia , Fibras Musgosas Hipocampais/patologia , Deficiência de Proteína/patologia , Animais , Peso Corporal , Encéfalo/patologia , Doença Crônica , Feminino , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Valores de ReferênciaRESUMO
PURPOSE: To characterize the long-term behavioral, electroencephalographic (EEG) and histopathologic features after a single TsTx microinjection into the hippocampus of rats. METHODS: TsTx, 2 microg, or 1 microl of 0.1 M phosphate buffer was injected into the right dorsal hippocampus of the rat. EEG records and behavioral observations were made over a period of 10 h after injection. For a period of 4 months, the animals were observed for the occurrence of convulsive seizures. At the end of the experiment, the brains were processed by the neo-Timm and Nissl methods. RESULTS: After intrahippocampal TsTx injection, three distinct phases were observed: (a) an immediate period that lasted 1 day, during which the motor and electrographic seizures characteristic of status epilepticus (SE) were seen; (b) a silent period (31-49 days), characterized by normal EEG and behavior; and (c) a period of spontaneous recurrent seizures (SRSs). The seizure frequency was one to two per week. Four months after TsTx injection, hippocampal neuronal loss and mossy fiber sprouting in the supragranular layer of the dentate gyrus were observed. CONCLUSIONS: The SRSs observed in this study may be associated with the TsTx-induced SE and brain damage. All animals injected with the toxin showed massive pyramidal neuronal loss in the dorsal hippocampus as well as intense gliosis and atrophy. Mossy fiber sprouting in the supragranular layer of the dentate gyrus was observed in those animals that had SRSs. The effects observed may be due, at least in part, to TsTx-enhanced release of glutamate in hippocampal pathways.
Assuntos
Convulsivantes/toxicidade , Hipocampo/efeitos dos fármacos , Fibras Musgosas Hipocampais/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Neurotoxinas/toxicidade , Venenos de Escorpião/toxicidade , Convulsões/induzido quimicamente , Estado Epiléptico/induzido quimicamente , Animais , Morte Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Eletroencefalografia/efeitos dos fármacos , Hipocampo/patologia , Masculino , Microinjeções , Fibras Musgosas Hipocampais/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Convulsões/patologia , Estado Epiléptico/patologiaRESUMO
Aberrant mossy fiber sprouting, which presumably results from hilar mossy cell death after status epilepticus (SE), is a frequently studied feature of temporal lobe epilepsy. Although mossy fiber sprouting can be suppressed by the protein synthesis inhibitor cycloheximide, spontaneous seizures remain unaltered. We have investigated the mechanisms underlying the ability of cycloheximide to block SE-induced mossy fiber sprouting in the inner molecular layer of dentate gyrus (IML). Pilocarpine-induced SE in the presence of cycloheximide resulted in a reduced number of injured hilar cells compared to rats not pretreated with cycloheximide. Presumed mossy cells, identified by calcitonin gene related peptide (CGRP) immunohistochemistry, were not significantly reduced in either group 60 days after SE. Whereas controls had a strong band of CGRP-positive fibers (putative mossy cell axons) and no neo-Timm stained fibers in the IML, pilocarpine-treated rats had no CGRP fibers and strong neo-Timm staining. Cycloheximide-pilocarpine-treated animals, in contrast, had CGRP and neo-Timm staining similar to controls. Cycloheximide might protect hilar CGRP-positive cells during SE and, by allowing those cells to retain their normal axonal projection, prevent mossy fiber sprouting. The recently suggested "irritable" mossy cell hypothesis relies on the survival of mossy cells for network hyperexcitability. We hypothesized that CGRP may be a marker for a subpopulation of relatively resistant mossy cells in rats, which, if they survive injury, may become irritable and contribute to hyperexcitability. We suggest that cycloheximide prevents SE-induced mossy fiber sprouting by preventing the loss of hilar CGRP-positive cells (putative mossy cells).