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1.
Ann Neurol ; 64(6): 687-97, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19107990

RESUMEN

OBJECTIVE: Chronic seizures in women can have adverse effects on reproductive function, such as polycystic ovarian syndrome, but it has been difficult to dissociate the effects of epilepsy from the role of antiepileptic drugs. To distinguish the effects of chronic seizures from medication, we used the laboratory rat, because an epileptic condition can be induced without concomitant anticonvulsant drug treatment. METHODS: Adult female rats were administered the chemoconvulsant pilocarpine to initiate status epilepticus, which was decreased in severity by the anticonvulsant diazepam. These rats developed spontaneous seizures in the ensuing weeks, and are therefore termed epileptic. Controls were saline-treated rats, or animals that were injected with pilocarpine but did not develop status epilepticus. Ovarian cyclicity and weight gain were evaluated for 2 to 3 months. Serum hormone levels were assayed from trunk blood, which was collected at the time of death. Paraformaldehyde-fixed ovaries were evaluated quantitatively. RESULTS: Rats that had pilocarpine-induced seizures had an increased incidence of acyclicity by the end of the study, even if status epilepticus did not occur. Ovarian cysts and weight gain were significantly greater in epileptic than control rats, whether rats maintained cyclicity or not. Serum testosterone was increased in epileptic rats, but estradiol, progesterone, and prolactin were not. INTERPRETATIONS: The results suggest that an epileptic condition in the rat leads to increased body weight, cystic ovaries, and increased testosterone levels. Although caution is required when comparing female rats with women, the data suggest that recurrent seizures have adverse effects, independent of antiepileptic drugs.


Asunto(s)
Modelos Animales de Enfermedad , Reproducción/fisiología , Convulsiones/fisiopatología , Animales , Epilepsia/sangre , Epilepsia/complicaciones , Epilepsia/fisiopatología , Femenino , Hormonas Esteroides Gonadales/sangre , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/etiología , Síndrome del Ovario Poliquístico/fisiopatología , Ratas , Ratas Sprague-Dawley , Convulsiones/sangre , Convulsiones/complicaciones
2.
Brain Res Bull ; 76(1-2): 36-44, 2008 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-18395608

RESUMEN

Previous studies have shown that VEGF expression in forebrain increases after experimental manipulations that increase neuronal activity. One question is whether this also occurs in motor neurons. If so, it could be potentially advantageous from a therapeutic perspective, because VEGF prevents motor neuron degeneration. Therefore, we asked whether endogenous VEGF expression in motor neurons could be modulated. We also asked how VEGF exposure would influence motor neurons using electrophysiology. Immunocytochemistry showed that motor neuron VEGF expression increased after a stimulus that increases neuronal and motor activity, i.e., convulsive seizures. The increase in VEGF immunoreactivity occurred in all motor neuron populations that were examined 24h later. This effect was unlikely to be due to seizure-induced toxicity, because silver degeneration stain did not show the typical appearance of a dying or dead neuron. To address the effects of VEGF on motor neuron function, VEGF was applied directly to motor neurons while recording intracellularly, using a brainstem slice preparation. Exposure to exogenous VEGF (200 ng/ml) in normal conditions depressed stimulus-evoked depolarization of hypoglossal motor neurons. There was no detectable effect of VEGF on membrane properties or firing behavior. We suggest that VEGF is upregulated in neurons when they are strongly activated, and VEGF depresses neuronal excitation as a compensatory mechanism. Failure of this mechanism may contribute to diseases that involve a dysregulation of VEGF, excessive excitation of motor neurons, and motor neuron loss, such as amyotrophic lateral sclerosis (ALS).


Asunto(s)
Electrofisiología , Neuronas Motoras/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Tronco Encefálico/citología , Humanos , Masculino , Neuronas Motoras/citología , Ratas , Ratas Sprague-Dawley , Convulsiones/metabolismo
3.
Eur J Neurosci ; 26(9): 2595-612, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17970745

RESUMEN

In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus.


Asunto(s)
Potenciales de Acción/fisiología , Estradiol/farmacología , Hipocampo/metabolismo , Neuronas/metabolismo , Ovulación/fisiología , Proestro/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Diestro/efectos de los fármacos , Diestro/metabolismo , Relación Dosis-Respuesta a Droga , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Hipocampo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Fibras Musgosas del Hipocampo/efectos de los fármacos , Fibras Musgosas del Hipocampo/metabolismo , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Técnicas de Cultivo de Órganos , Ovariectomía , Ovulación/efectos de los fármacos , Proestro/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Tiempo
4.
Eur J Neurosci ; 24(8): 2203-10, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17042797

RESUMEN

Following status epilepticus in the rat, dentate granule cell neurogenesis increases greatly, and many of the new neurons appear to develop ectopically, in the hilar region of the hippocampal formation. It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after status epilepticus. However, the population has never been quantified, so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis. To quantify this population, the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after pilocarpine-induced status epilepticus. The number of hilar neurons immunoreactive for Prox-1, a granule-cell-specific marker, was estimated using the optical fractionator method. The results indicate that the size of the hilar ectopic granule cell population after status epilepticus is substantial, and stable over time. Interestingly, the size of the population appears to be correlated with the frequency of behavioral seizures, because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures. The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis, although it is associated with an increase in volume of the hilus. The results provide new insight into the potential role of ectopic hilar granule cells in the pilocarpine model of temporal lobe epilepsy.


Asunto(s)
Hipocampo/patología , Agonistas Muscarínicos , Pilocarpina , Estado Epiléptico/patología , Algoritmos , Animales , Conducta Animal/efectos de los fármacos , Recuento de Células , Tamaño de la Célula , Gránulos Citoplasmáticos/patología , Giro Dentado/patología , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica , Masculino , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/inducido químicamente , Fijación del Tejido , Proteínas Supresoras de Tumor
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