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We use the Low Frequency Array (LOFAR) to probe the dynamics of the stepping process of negatively charged plasma channels (negative leaders) in a lightning discharge. We observe that at each step of a leader, multiple pulses of vhf (30-80 MHz) radiation are emitted in short-duration bursts (<10 µs). This is evidence for streamer formation during corona flashes that occur with each leader step, which has not been observed before in natural lightning and it could help explain x-ray emission from lightning leaders, as x rays from laboratory leaders tend to be associated with corona flashes. Surprisingly, we find that the stepping length is very similar to what was observed near the ground, however with a stepping time that is considerably larger, which as yet is not understood. These results will help to improve lightning propagation models, and eventually lightning protection models.
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We investigate the launch of negative upward streamers from sprite glows. This phenomenon is readily observed in high-speed observations of sprites and underlies the classification of sprites into carrot or column types. First, we describe how an attachment instability leads to a sharply defined region in the upper part of the streamer channel. This region has an enhanced electric field, low conductivity and strongly emits in the first positive system of molecular nitrogen. We identify it as the sprite glow. We then show how, in the most common configuration of a carrot sprite, several upward streamers emerge close to the lower boundary of the glow, where negative charge gets trapped and the lateral electric field is high enough. These streamers cut off the current flowing toward the glow and lead to the optical deactivation of the glow above. Finally, we discuss how our results naturally explain angel sprites.
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We present measurements of radio emission from cosmic ray air showers that took place during thunderstorms. The intensity and polarization patterns of these air showers are radically different from those measured during fair-weather conditions. With the use of a simple two-layer model for the atmospheric electric field, these patterns can be well reproduced by state-of-the-art simulation codes. This in turn provides a novel way to study atmospheric electric fields.
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In a paediatric population, the successful management of childhood atopic dermatitis (AD) should include the careful evaluation and selection of available therapies, based not only on demonstrated safety and tolerability in small children and infants, but also on their evidence-based, anti-pruritic benefits. Moreover, the speed of anti-pruritic effect should be considered a significant parameter in treatment selection. The fourth-generation topical corticosteroid (TC) methylprednisolone aceponate (MPA) is a potent anti-inflammatory agent with a demonstrated fast and effective itch relief profile in children and infants (as young as 2 months) with AD. Compared with traditional TCs, MPA has a significantly improved therapeutic index; that is, increased potency without a proportionate increase in side effects. In addition to its established efficacy, the once-daily application and broad range of available formulations make MPA an optimal choice for acute and maintenance therapy in paediatric patients with AD-related pruritus.
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Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Metilprednisolona/análogos & derivados , Prurido/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Dermatite Atópica/fisiopatologia , Humanos , Lactente , Metilprednisolona/uso terapêutico , Prurido/fisiopatologiaRESUMO
An analysis is presented of electric fields in thunderclouds using a recently proposed method based on measuring radio emission from extensive air shower events during thunderstorm conditions. This method can be regarded as a tomography of thunderclouds using cosmic rays as probes. The data cover the period from December 2011 till August 2014. We have developed an improved fitting procedure to be able to analyze the data. Our measurements show evidence for the main negative-charge layer near the -10° isotherm. This we have seen for a winter as well as for a summer cloud where multiple events pass through the same cloud and also the vertical component of the electric field could be reconstructed. On the day of measurement of some cosmic-ray events showing evidence for strong fields, no lightning activity was detected within 100 km distance. For the winter events, the top heights were between 5 and 6 km, while in the summer, typical top heights of 9 km were seen. Large horizontal components in excess of 70 kV/m of the electric fields are observed in the middle and top layers.
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Lightning mapping technology has proven instrumental in understanding lightning. In this work we present a pipeline that can use lightning observed by the LOw-Frequency ARray (LOFAR) radio telescope to construct a 3-D map of the flash. We show that LOFAR has unparalleled precision, on the order of meters, even for lightning flashes that are over 20 km outside the area enclosed by LOFAR antennas (â¼3,200 km2), and can potentially locate over 10,000 sources per lightning flash. We also show that LOFAR is the first lightning mapping system that is sensitive to the spatial structure of the electrical current during individual lightning leader steps.
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The piriform cortex (PC) is the largest region of the mammalian olfactory cortex with strong connections to other limbic structures, including the amygdala, hippocampus, and entorhinal cortex. In addition to its functional importance in the classification of olfactory stimuli, the PC has been implicated in the study of memory processing, spread of excitatory information, and the facilitation and propagation of seizures within the limbic system. Previous data from the kindling model of epilepsy indicated that alterations in GABAergic inhibition in the transition zone between the anterior and posterior PC, termed here central PC, are particularly involved in the processes underlying seizure propagation. In the present study we studied alterations in GABAergic neurons in different parts of the PC following seizures induced by kainate or pilocarpine in rats. GABA neurons were labeled either immunohistochemically for GABA or its synthesizing enzyme glutamate decarboxylase (GAD) or by in situ hybridization using antisense probes for GAD65 and GAD67 mRNAs. For comparison with the PC, labeled neurons were examined in the basolateral amygdala, substantia nigra pars reticulata, and the hippocampal formation. In the PC of controls, immunohistochemical labeling for GABA and GAD yielded consistently higher neuronal densities in most cell layers than labeling for GAD65 or GAD67 mRNAs, indicating a low basal activity of these neurons. Eight hours following kainate- or pilocarpine-induced seizures, severe neuronal damage was observed in the PC. Counting of GABA neurons in the PC demonstrated significant decreases in densities of neurons labeled for GABA or GAD proteins. However, a significantly increased density of neurons labeled for GAD65 and GAD67 mRNAs was determined in layer II of the central PC, indicating that a subpopulation of remaining neurons up-regulated the mRNAs for the GAD isoenzymes. One likely explanation for this finding is that remaining GABA neurons in layer II of the central PC maintain high levels of activity to control the increased excitability of the region. In line with previous studies, an up-regulation of GAD67 mRNA, but not GAD65 mRNA, was observed in dentate granule cells following seizures, whereas no indication of such up-regulation was determined for the other brain regions examined. The data substantiate the particular susceptibility of the central PC to seizure-induced plasticity and indicate that this brain region provides an interesting tool to study the regulation of GAD isoenzymes.
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Regulação da Expressão Gênica/fisiologia , Glutamato Descarboxilase/metabolismo , Neurônios/metabolismo , Condutos Olfatórios/patologia , Estado Epiléptico/patologia , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Animais , Contagem de Células/métodos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamato Descarboxilase/genética , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Isoenzimas/genética , Isoenzimas/metabolismo , Ácido Caínico/toxicidade , Condutos Olfatórios/metabolismo , Pilocarpina/toxicidade , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismoRESUMO
In epilepsy research, there is growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures, i.e. the most common type of seizures in human epilepsy. The PC ("primary olfactory cortex") is the largest area of the mammalian olfactory cortex and receives direct projections from the olfactory bulb via the lateral olfactory tract (LOT). Beside the obvious involvement in olfactory perception and discrimination, the PC, because of its unique intrinsic associative fiber system and its various connections to and from other limbic nuclei, has been implicated in the study of memory processing, spread of excitatory waves, and in the study of brain disorders such as epilepsy with particular emphasis on the kindling model of temporal lobe epilepsy with complex partial seizures. The interest in the kindling model is based primarily on the following observations. (1) The PC contains the most susceptible neural circuits of all forebrain regions for electrical (or chemical) induction of limbic seizures. (2) During electrical stimulation of other limbic brain regions, broad and large afterdischarges can be observed in the ipsilateral PC, indicating that the PC is activated early during the kindling process. (3) The interictal discharge, which many consider to be the hallmark of epilepsy, originates in the PC, independent of which structure serves as the kindled focus. (4) Autoradiographic studies of cerebral metabolism in rat amygdala kindling show that, during focal seizures, the area which exhibits the most consistent increase in glucose utilization is the ipsilateral paleocortex, particularly the PC. (5) During the commonly short initial afterdischarges induced by stimulation of the amygdala at the early stages of kindling, the PC is the first region that exhibits induction of immediate-early genes, such as c-fos. (6) The PC is the most sensitive brain structure to brain damage by continuous or frequent stimulation of the amygdala or hippocampus. (7) Amygdala kindling leads to a circumscribed loss of GABAergic neurons in the ipsilateral PC, which is likely to explain the increase in excitability of PC pyramidal neurons during kindling. (8) Kindling of the amygdala or hippocampus induces astrogliosis in the PC, indicating neuronal death in this brain region. Furthermore, activation of microglia is seen in the PC after amygdala kindling. (9) Complete bilateral lesions of the PC block the generalization of seizures upon kindling from the hippocampus or olfactory bulb. Incomplete or unilateral lesions are less effective in this regard, but large unilateral lesions of the PC and adjacent endopiriform nucleus markedly increase the threshold for induction of focal seizures from stimulation of the basolateral amygdala (BLA) prior to and after kindling, indicating that the PC critically contributes to regulation of excitability in the amygdala. (10) Potentiation of GABAergic neurotransmission in the PC markedly increases the threshold for induction of kindled seizures via stimulation of the BLA, again indicating a critical role of the PC in regulation of seizure susceptibility of the amygdala. Microinjections of NMDA antagonists or sodium channel blockers into the PC block seizure generalization during kindling development. (11) Neurophysiological studies on the amygdala-PC slice preparation from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility to evoked burst responses. The epileptiform potentials in PC slice preparations from kindled rats seem to originate in neuron at the deep boundary of PC. Spontaneous firing and enhanced excitability of PC neurons in response to kindling from other sites is also seen in vivo, substantiating the fact that kindling induces long-lasting changes in the PC c
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Córtex Cerebral/fisiopatologia , Epilepsia/fisiopatologia , Excitação Neurológica/fisiologia , Animais , Humanos , RatosRESUMO
The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survival-despite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/breast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition.
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Anormalidades Induzidas por Medicamentos/etiologia , Antineoplásicos/uso terapêutico , Antirreumáticos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Antineoplásicos/efeitos adversos , Feminino , Humanos , Gravidez , Resultado da GravidezRESUMO
BACKGROUND: Human patients with limbic epilepsy may develop a psychosis. We combined animal models for epileptogenesis and schizophrenia to investigate possible mechanisms underlying the occurrence of psychoses in epileptics. Since the dysfunction of sensorimotor gating is the basis of some psychotic symptoms, we tested if epileptogenesis or acute seizures influence sensorimotor gating in rats, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is the reduction of the ASR that is observed when a startling pulse is preceded by a nonstartling prepulse. Reduced PPI was found in schizophrenics and in rats under certain conditions. METHODS: We investigated the effects on PPI of different models of limbic epileptogenesis (repeated stimulation of the basolateral amygdala, treatment with pentylenetetrazole, injection of kainate). RESULTS: PPI was normal in chronic epileptic rats 1 week after the last generalized seizure. Impaired PPI was found in amygdala-kindled rats 10 min after seizures. The ASR amplitude in the absence of prepulses was increased in kainate-treated rats, but not in the other groups. CONCLUSIONS: Chemical epileptogenesis or repeated stimulation of the amygdala per se did not disrupt sensorimotor gating, but the recent occurrence of seizures in amygdala-kindled rats compromised sensorimotor gating in a way compatible with psychotic states in humans.
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Tonsila do Cerebelo , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/fisiopatologia , Excitação Neurológica/fisiologia , Reflexo de Sobressalto/fisiologia , Esquizofrenia/fisiopatologia , Estimulação Acústica , Análise de Variância , Animais , Sinais (Psicologia) , Estimulação Elétrica , Epilepsia do Lobo Temporal/complicações , Feminino , Inibição Psicológica , Ácido Caínico , Pentilenotetrazol , Ratos , Ratos Wistar , Esquizofrenia/complicações , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
OBJECTIVE: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent antagonist of midazolam-induced sedation. Physostigmine has also been shown to reverse benzodiazepine sedation in anecdotal reports. The aim of this study was to quantitatively characterize the reversal of midazolam-induced changes in electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo. METHODS: Twelve healthy male subjects received 5 mg midazolam as an intravenous infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline solution) were administered as intravenous injections in a randomized crossover fashion. Midazolam serum concentrations were measured using liquid chromatography-tandem mass spectrometry. The time from the start of injection until awakening was noted and the EEG was measured. RESULTS: Four subjects were excluded from further pharmacokinetic and pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power could be observed in each of the three study periods. The pharmacokinetics of midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P < .05). After injection of flumazenil and physostigmine, an increase in EEG alpha power was observed, whereas placebo did not affect alpha power. Subjects opened their eyes 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received flumazenil and physostigmine, respectively (mean +/- SEM; P < .001). CONCLUSION: Physostigmine and flumazenil antagonized midazolam-induced sedation. This suggests that a reversible central anticholinergic mechanism may be involved in the sedative action of midazolam.
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Antídotos/farmacologia , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Hipnóticos e Sedativos/antagonistas & inibidores , Midazolam/antagonistas & inibidores , Fisostigmina/farmacologia , Adulto , Análise de Variância , Cromatografia Líquida , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia/efeitos dos fármacos , Flumazenil/farmacologia , Humanos , Hipnóticos e Sedativos/sangue , Hipnóticos e Sedativos/farmacocinética , Infusões Intravenosas , Masculino , Midazolam/sangue , Midazolam/farmacocinética , Valores de ReferênciaRESUMO
We evaluated the anticonvulsant efficacy of the antiepileptic drugs (AEDs) lamotrigine (LTG) and felbamate (FBM) in amygdala kindled rats that had been preselected with respect to their response to phenytoin. Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e., a sensitive measure for drug effects on focal seizure activity. By repeated testing with the phenytoin prodrug fosphenytoin, 3 groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (phenytoin responders), rats which showed no anticonvulsant response (phenytoin nonresponders), and rats with variable responses (variable phenytoin responders). The latter, largest group was used to evaluate at which doses LTG and FBM exerted significant anticonvulsant effects on ADT 1 h after i.p. drug administration. Effective doses were then used for drug testing in phenytoin responders and nonresponders. Both LTG and FBM proved to be effective anticonvulsant drugs in the kindling model by markedly increasing the ADT. Seizure severity and duration recorded at ADT currents were hardly reduced, indicating that both drugs predominantly affect induction of focal seizures and not seizure spread from the focus. In phenytoin nonresponders, LTG and FBM significantly increased ADT, which is in line with their proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, LTG and, more markedly, FBM were clearly more efficacious in increasing ADT in phenytoin responders than in nonresponders, substantiating that the difference in phenytoin response between these groups of kindled rats extends to other AEDs. The data in this study reveal that phenytoin nonresponders are a unique model for the search for new AEDs with improved efficacy in refractory partial epilepsy.
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Anticonvulsivantes/farmacologia , Excitação Neurológica/efeitos dos fármacos , Fenitoína/farmacologia , Propilenoglicóis/farmacologia , Triazinas/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Estimulação Elétrica , Eletrodos Implantados , Epilepsias Parciais/fisiopatologia , Felbamato , Feminino , Lamotrigina , Fenilcarbamatos , Ratos , Ratos WistarRESUMO
The discovery that glutamate's activity at the N-methyl-D-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine(B) receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine, receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine, receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10-40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25-5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.
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2-Amino-5-fosfonovalerato/análogos & derivados , Tonsila do Cerebelo/fisiologia , Anticonvulsivantes/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Excitação Neurológica/efeitos dos fármacos , Piperidinas/farmacologia , Quinolonas/farmacologia , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Interações Medicamentosas , Feminino , Excitação Neurológica/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
About 20-30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms explaining why some patients' respond and others prove resistant to antiepileptic drugs are poorly understood. It has been proposed that pharmacoresistance is related to reduced sensitivity of sodium channels in hippocampal neurons to antiepileptic drugs such as carbamazepine or phenytoin. In line with this proposal, a reduced effect of carbamazepine on sodium currents in hippocampal CA1 neurons was found in the rat kindling model of temporal lobe epilepsy (TLE), i.e. a form of epilepsy with the poorest prognosis of all epilepsy types in adult patients. To address directly the possibility that neuronal sodium currents in the hippocampus play a crucial role in the pharmacoresistance of TLE, we selected amygdala-kindled rats with respect to their in vivo anticonvulsant response to phenytoin into responders and nonresponders and then compared phenytoin's effect on voltage-activated sodium currents in CA1 neurons. Furthermore, in view of the potential role of calcium current modulation in the anticonvulsant action of phenytoin, the effect of phenytoin on high-voltage-activated calcium currents was studied in CA1 neurons. Electrode-implanted but not kindled rats were used as sham controls for comparison with the kindled rats. In all experiments, the interval between last kindled seizure and ion channel measurements was at least 5 weeks. In kindled rats with in vivo resistance to the anticonvulsant effect of phenytoin (phenytoin nonresponders), in vitro modulation of sodium and calcium currents by phenytoin in hippocampal CA1 neurons did not significantly differ from respective data obtained in phenytoin responders, i.e. phenytoin resistance was not associated with a changed modulation of the sodium or calcium currents by this drug. Compared to sham controls, phenytoin's inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and nonresponder subgroups. Further studies in phenytoin-resistant kindled rats may help to elucidate the mechanisms that can explain therapy resistance.
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Anticonvulsivantes/farmacologia , Canais de Cálcio/metabolismo , Hipocampo/metabolismo , Excitação Neurológica/fisiologia , Neurônios/metabolismo , Fenitoína/farmacologia , Canais de Sódio/metabolismo , Animais , Canais de Cálcio/efeitos dos fármacos , Resistência a Medicamentos , Eletrodos Implantados , Eletrofisiologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Canais de Sódio/efeitos dos fármacosRESUMO
The piriform cortex (PC) is the largest region of the mammalian olfactory cortex with strong connections to limbic structures, including the amygdala, hippocampus, and entorhinal cortex. Various previous studies in rodents suggest that the PC might be very important in the development and maintenance of limbic kindling, i.e. a widely used model of temporal lobe epilepsy. GABAergic inhibition in the transition zone between the anterior and posterior PC, termed here central PC, seems to be particularly involved in the processes leading to progression of kindled seizures. This prompted us to study whether elevation of GABA levels in this subregion of the PC by bilateral microinjection of vigabatrin is capable of suppressing amygdala kindling. Rats were stimulated once daily until fully kindled (stage 5) seizures had developed. Vigabatrin (10 microg) was injected 24 h before the first stimulation as well as 6 h before the 5th and 10th stimulation, which approximately doubled the number of stimulations required for kindling development compared with controls. This marked retardation of kindling acquisition was predominantly due to a significant inhibition of the progression from stage 1 to stage 2 and stage 3 to stage 4 seizures, demonstrating that microinjection of vigabatrin into the central PC markedly inhibits the progression and secondary generalization of focal seizures emanating from the amygdala.
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Tonsila do Cerebelo/fisiologia , Anticonvulsivantes/farmacologia , Agonistas GABAérgicos/farmacologia , Excitação Neurológica/fisiologia , Condutos Olfatórios/fisiologia , Vigabatrina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Anticonvulsivantes/administração & dosagem , Eletrodos Implantados , Feminino , Agonistas GABAérgicos/administração & dosagem , Excitação Neurológica/efeitos dos fármacos , Microinjeções , Condutos Olfatórios/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/fisiopatologia , Vigabatrina/administração & dosagem , Ácido gama-Aminobutírico/fisiologiaRESUMO
The piriform cortex (PC) is thought to be critically involved in the generation and propagation of forebrain (limbic type) seizures in the rat. The PC extends over a large area at the ventrolateral side of the rat brain with an anterior part highly sensitive for bicuculline-induced and a central part most sensitive for electrically induced seizures. Therefore, distinct parts of the PC might be differentially involved in the generation and spread of seizure activity. Since previous studies indicated that a loss of GABAergic inhibition in the PC is involved in the generation of epileptic activity, we microinjected the GABA-transaminase blocker vigabatrin bilaterally in the anterior, central and posterior PC of previously amygdala-kindled rats and repeatedly tested its effect on kindled seizures. Vigabatrin was anticonvulsant in all groups for up to 13 days with a maximal effect 24 h after injection. However, the anticonvulsant effect on seizure generalization was strongest after microinjection in the central PC suggesting that GABAergic synapses in this part are critically involved in the development of generalized seizures. Since differences in anatomical connections of the PC regions may be responsible for differences in seizure susceptibility, we addressed this question by injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin in different PC subregions. Although there were similarities in the projections from different PC subregions, we also found differences between the PC subregions in their projections to structures known to be important in the limbic seizure network, such as the perirhinal cortex, nucleus accumbens, and striatum. These differences in anatomical connectivity between PC subregions may be involved in the differences in seizure susceptibility observed in the present and previous studies.
Assuntos
Anticonvulsivantes/administração & dosagem , Excitação Neurológica/efeitos dos fármacos , Condutos Olfatórios/anatomia & histologia , Vigabatrina/administração & dosagem , Ácido gama-Aminobutírico/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/fisiopatologia , Feminino , Injeções Intraventriculares , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Condutos Olfatórios/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The piriform cortex is thought to be involved in temporal lobe seizure propagation, such as that occurring during kindling of the amygdala or hippocampus. A number of observations suggested that the circuits of the piriform cortex might act as a critical pathway for limbic seizure discharges to assess motor systems, but direct evidence for this suggestion is scarce. Furthermore, the piriform cortex is not a homogeneous structure, which complicates studies on its role in limbic epileptogenesis. We have previously reported data indicating that the central part of the piriform cortex might be particularly involved during amygdala kindling. In order to further evaluate the role of different parts of the piriform cortex during kindling development, we bilaterally destroyed either the central, anterior or posterior piriform cortex by microinjections of ibotenate two weeks before onset of amygdala kindling. Lesions of the anterior piriform cortex hardly affected kindling acquisition, except that fewer animals exhibited stage 3 (unilateral forelimb) seizures compared to sham controls. Lesions of the central piriform cortex significantly retarded kindling, which was due to a decreased progression from stage 3 to stage 4/5 seizures, i.e. the lesioned rats needed significantly longer for the acquisition of generalized clonic seizures in the late stages of kindling development. Lesions of the posterior piriform cortex did not significantly affect kindling development. The data demonstrate that different parts of the piriform cortex mediate qualitatively different effects on amygdala kindling. The central piriform cortex seems to be a neural substrate involved in the continuous development of kindling from stage 3 to stages 4/5, indicating that this part of the piriform cortex may have preferred access, either directly or indirectly, to structures capable of supporting generalized kindled seizure expression.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Excitação Neurológica/fisiologia , Vias Neurais/fisiopatologia , Condutos Olfatórios/fisiopatologia , Convulsões/fisiopatologia , Tonsila do Cerebelo/patologia , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Feminino , Ácido Ibotênico/efeitos adversos , Excitação Neurológica/patologia , Vias Neurais/patologia , Condutos Olfatórios/patologia , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/patologiaRESUMO
Several lines of evidence suggest that the piriform cortex functions as a generator in the development and propagation of forebrain (limbic type) seizures, particularly in the kindling model of epilepsy. It is, however, not clear where, within the rather large piriform cortex region, the generator resides, and how much tissue is involved. Highly sensitive loci to chemical or electrical stimulation have been described both in the deep anterior and posterior parts of the piriform cortex. Furthermore, data from piriform cortex slice preparations indicated that epileptiform potentials originate in deep structures, particularly the endopiriform nucleus that underlies the piriform cortex. In the present study, in rats, we implanted stimulation and recording electrodes in various rostrocaudal locations of the piriform cortex and endopiriform nucleus, including the "area tempestas", i.e. a structure in the anterior part of the piriform cortex previously proposed to be critically involved in the generation of convulsive seizures of limbic origin. Within the piriform cortex, electrodes were aimed at different cellular layers of this structure. For comparison, additional animals received electrodes in different parts of the basolateral amygdala. A total of 19 different locations was obtained in this way. The susceptibility of these locations to electrical stimulation was characterized by determining the threshold for induction of afterdischarges. The afterdischarge threshold was lowest in layer III of the posterior piriform cortex and some locations in the endopiriform nucleus, whereas amygdala and "area tempestas" displayed higher values. In several animals, particularly those with electrodes in layer III of the posterior piriform cortex, spontaneous spiking was seen in prestimulation recordings, whereas this was never observed in recordings from the amygdala. Subsequent kindling by repeated stimulation of the various locations demonstrated marked differences in afterdischarge threshold reduction and kindling rate. The most marked decreases in afterdischarge threshold were seen in locations within layer III of the piriform cortex, whereas several other locations, including the "area tempestas", exhibited only moderate decreases or no decrease at all. In contrast to previous observations with only few locations in the piriform cortex region, the posterior piriform cortex was not in general slower to kindle than the anterior piriform cortex, although some locations in the posterior piriform cortex exhibited significantly lower kindling rates than the amygdala. The highest kindling rate was seen in the dorsal endopiriform nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Tonsila do Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Excitação Neurológica/fisiologia , Animais , Condutividade Elétrica , Eletrodos , Feminino , Prosencéfalo/fisiopatologia , Ratos , Ratos Wistar , Convulsões/fisiopatologia , Fatores de TempoRESUMO
Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus. The massive neurodegeneration in the hippocampus is known as hippocampal sclerosis, and is considered one of the hallmarks of this type of difficult-to-treat epilepsy. There is a long and ongoing debate on whether this sclerosis is the result of an initial pathological event, such as a status epilepticus (S.E.), stroke or head trauma, which often precedes the development of TLE, or is caused by the spontaneous recurrent seizures (SRS) once epilepsy has developed. At present, pharmacological prevention of limbic sclerosis is not available. In a clinical situation, such prevention would only be possible if delayed cell death developing after an initial pathological event is involved. Assuming that sclerotic brain lesions provoke epileptogenesis and that delayed cell death is involved in these lesions, it should be possible to prevent both the lesions and the epilepsy by a prophylactic treatment after an initial insult such as an S.E. In order to test this hypothesis, we used a rat model of TLE in which limbic brain lesions and epilepsy with SRS develop after a kainate-induced S.E. A single low dose of the N-methyl-D-aspartate (NMDA) receptor blocker dizocilpine (MK-801) significantly reduced the damage in limbic regions, including the hippocampus and piriform cortex, and completely protected several rats from such damage when given after an S.E. of 90 min induced by kainate, strongly suggesting that delayed cell death is involved in the damage. This was substantiated by the use of molecular and immunohistochemical markers of delayed active ("programmed") cell death. However, the neuroprotection by dizocilpine did not prevent the development of SRS after the S.E., suggesting that structures not protected by dizocilpine may play a role in the genesis of SRS or that epileptogenesis is not the consequence of structural lesions in the limbic system. The only brain regions that exhibited neuronal damage in all rats with SRS were the hilus of the dentate gyrus and the mediodorsal thalamus, although treatment with dizocilpine reduced the severity of damage in the latter region. The data indicate that NMDA receptor blockade immediately after a prolonged S.E. is an effective means to reduce the damage produced by a sustained S.E. in several brain regions, including the hippocampus, but show that this partial neuroprotection of the limbic system does not prevent the development of epilepsy.
Assuntos
Epilepsia do Lobo Temporal/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistema Límbico/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estado Epiléptico/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Fragmentação do DNA/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/uso terapêutico , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Ácido Caínico/antagonistas & inibidores , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatologia , Núcleo Mediodorsal do Tálamo/efeitos dos fármacos , Núcleo Mediodorsal do Tálamo/metabolismo , Núcleo Mediodorsal do Tálamo/patologia , Degeneração Neural/metabolismo , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/metabolismo , Condutos Olfatórios/patologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/fisiopatologia , Resultado do TratamentoRESUMO
Sprouting of mossy fibers in the hippocampus of rats that underwent limbic epileptogenesis by amygdala kindling or kainate injection was studied at the light microscopic and ultrastructural levels by cytochemical demonstration of the enzyme 5'-nucleotidase. This adenosine-producing ectoenzyme has previously been shown to characterize malleable terminals during brain development and lesion-induced synaptogenesis, but to be otherwise associated with glial membranes. At the light microscopic level, kainate-treated but not control or kindled rats showed 5'-nucleotidase activity in the CA3 region and in the inner molecular layer of the dentate gyrus. At the ultrastructural level, in control animals, the synapses of the molecular and granular layers were enzyme negative. Only some mossy fiber boutons of the dentate hilus exhibited 5'-nucleotidase activity. In epileptic rats, synaptic labeling within the hilus appeared more intense. Moreover, 5'-nucleotidase-containing terminals within the inner molecular layer, presumably ectopic mossy fiber boutons, were found in both kindled and kainate-treated rats. It is concluded that, in both the normal and epileptic hippocampus, 5'-nucleotidase is associated with axons capable of a plastic sprouting response. The synaptic enzyme may attenuate the glutamatergic transmission of mossy fibers, in particular of the aberrant mossy fibers in epileptic rats, by producing the inhibitory neuromodulator adenosine. Alternatively, 5'-nucleotidase may influence synapse formation by its putative non-enzymatic, adhesive functions.