胚胎NA能神经元移植对鼠点燃癫痫发作程度的影响

目的：明确胚胎NA能神经元移植对点燃癫痫发作严重程度的影响。方法：以Wistar大鼠为研究对象，按移植物的性质分为NA移植组、移植对照组和还对照组。首先定期电刺激杏仁核制备电点燃癫痫模型，再用立体定向技术向各组动物的海马移植相应的移植物，移植后观察癫痫的电生理和行为学指标（杏仁核后放电阈值、持续时间、癫痫行为级别、癫痫持续时间）变化情况，TH免疫组织化学染色了解移植物存活情况。结果：经统计学处理，移植前后各指标无显著性差异（P＞0．05）。结论：胚胎NA能神经元移植对点燃癫痫的发作严重程度无抑制作用。     

Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice

Brain cyclooxygenases (COX), the rate-limiting enzyme in prostaglandin synthesis, is rapidly and transiently induced by convulsions in hippocampal and cortical neurons. Previous studies have explored the protective effect of naproxen (non-selective COX-inhibitor) or rofecoxib (selective COX-2 inhibitor) against chemical kindling in mice. With this background, the present study was designed to explore the possible effect of nimesulide (a preferential COX-2 inhibitor) against pentylenetetrazol (PTZ)-induced kindling epilepsy in mice. To induce kindling, PTZ was injected in a subconvulsive dose (40 mg/kg, i.p.) every other day for 15 days. Nimesulide (2.5 or 5 mg/kg, p.o.) was administered each day 45 min before either PTZ or vehicle challenge. The intensity of kindling was assessed immediately after PTZ administration according to a prevalidated scoring scale. On 16th day i.e. 24 h after the last dose of PTZ, animals were sacrificed and various biochemical parameters were assessed in the whole brain. Compared with normal control group, PTZ-kindled mice had significantly higher levels of malondialdehyde, nitrite, myeloperoxidase but had lower levels of reduced glutathione in the whole brain homogenate. Chronic treatment with nimesulide (2.5 or 5 mg/kg, p.o.) for 15 days showed significant decrease in kindling score and could play a role in controlling the accompanying biochemical alterations due to PTZ. These results suggested that nimesulide, a preferential COX-2 inhibitor offered neuroprotection against PTZ-induced kindling in mice.     

Frontal versus transcorneal stimulation to induce maximal electroshock seizures or kindling in mice and rats

Frontal stimulation, i.e. electrical stimulation where electrodes are pressed on the skin of the intact frontal skull of mice or rats, may represent a more humane alternative to the widely used transcorneal stimulation to induce electroshock seizures. The aim of this work was to directly compare transcorneal and frontal stimulation in eliciting maximal electroshock-induced seizures (MES) in mice and the anticonvulsant effect of carbamazepine (CBZ) and phenytoin (PHT) on thus produced seizures. In addition, we stimulated mice and rats repeatedly via transcorneal and frontal electrodes to see whether kindling is produced by this procedure. Two electroshock tests were used in mice, i.e. maximal electroshock seizure threshold (MEST) test and MES generated by supramaximal stimulation (50 mA). Frontal stimulation resulted in lower convulsive threshold than in the case of corneal stimulation. Both CBZ and PHT produced dose-dependent increases in seizure threshold for both sites of stimulation, i.e. transcorneal and frontal. As regards type of electrodes, higher doses of PHT were required to increase seizure threshold in the case of frontal than transcorneal stimulation. Supramaximal stimulation (50 mA) yielded comparable ED₅₀ values regardless of the site of stimulation. Furthermore, once-daily stimulation of mice, regardless of the placement of electrodes, did not induce any changes in convulsive threshold. We also attempted to kindle mice and rats via corneal and frontal electrodes by repetitive electrical stimulation using currents which initially did not produce generalized clonic seizures. Mice were stimulated once daily for 2 s with 3 mA (corneal electrodes) or 2 mA (frontal electrodes) and rats were stimulated twice daily for 4 s at 8 mA (corneal electrodes) or 5 mA (frontal electrodes). With corneal stimulation in rats there was a clear progression of kindling development which was not the same in nature when compared with corneally-stimulated mice. Frontal stimulation did not produce kindling. Moreover, corneal stimulation was better tolerated by rats, while in mice high mortality was seen after either method of current delivery. Our data indicate that frontal electrodes can be used as an alternative to transcorneal stimulation to produce MES by supramaximal or threshold current intensities as screening procedures in antiepileptic drug (AED) development. Nevertheless, this type of stimulation cannot be used to produce minimal electroshock seizures and seems not to be useful to produce kindling in rats and mice.     

Synaptic modifications accompanying epileptogenesis in vitro: long-term depression of GABA-mediated inhibition

We used an in vitro model similar to kindling to examine the processes underlying epileptogenesis. A 60 Hz train was applied every 5–10 min to the Schaffer collateral pathways in guinea pig hippocampal slices until epileptiform bursting was elicited in the CA3 region. The resultant alterations in both spontaneous and evoked activities were studied using intracellular recordings from CA3 pyramidal cells. An attempt was made to elucidate the synaptic modifications responsible for the conversion to this state of enhanced excitability. Analyses revealed that the emergence of epileptiform discharge was accompanied by a long-term depression of evoked inhibitory conductances. This tetanus-induced reduction of inhibition involved both the early and late phases of the evoked hyperpolarization, suggesting modification of both the GABA_A and GABA_B receptor-mediated events. Previous studies have suggested that NMDA receptor activation plays an important role in the induction of epileptiform activity in this model. Our data, showing that depression of inhibition can be induced in the presence of CNQX, is consistent with this hypothesis. The parallel development of long-term depression of inhibition and epileptiform bursting following tetanic stimulation suggests that plasticity of the inhibitory transmission process is a potential source of vulnerability contributing to epileptogenesis.     

Stepwise progression of kindling: Perspectives from the kindling antagonism model

What is the nature of the kindling process? We hypothesize that kindling is a discontinuous process involving discrete, stepwise transitions from one state of neural organization to another. Our data from the kindling antagonism paradigm argue that there are two critical transitions in the kindling process. These transitions constitute major steps in kindled seizure development. They act as "gates" controlling the ability of afterdischarge (AD) activity to effect the necessary reorganization of neural function which drives the kindling process. We identify two critical gates: 1) a forebrain gate which is dependent on norepinephrine (NE) and effects a discrete transition from nonconvulsive, stage 1 and 2 behaviors to stage 3 seizures, and 2) a brainstem gate which is also NE-dependent and effects a transition from stage 3 seizures to stage 4 and 5 seizures. These gates separate the kindling process into 3 "phases" which are different from, but overlap, the traditional behavioral stages of kindling defined by Racine. Current data suggest that these phases involve independent neural circuitry. They may also involve different physiological mechanisms, but this remains to be determined. This hypothesis is designed to provide a framework for the kindling process within which to search for kindling mechanisms.     

The GABA hypothesis of kindling: Recent assay studies

The GABA (gamma-aminobutyric acid) hypothesis of kindling suggests that the permanent changes caused by the kindling procedure result from a loss of GABA-mediated inhibition. Pharmacological studies have generally supported this hypothesis: GABA-complex antagonists accelerate (or stimulate) kindling, whereas GABA-complex agonists retard (or reverse) it. Assay studies, however, have presented an inconsistent picture. Earlier studies found no GABAergic brain changes after kindling, whereas recent studies have reported postkindling changes in a number of GABA-related parameters. The crucial difference seems to be that earlier studies assayed GABA parameters in "whole tissue," whereas recent studies have concentrated on "synaptic" GABA. As indicated by recent studies, when the "metabolic pool" is excluded, kindled subjects show a variety of persistent abnormalities in the GABA system. These data are generally consistent with the GABA hypothesis of kindling.     

Relationship of some open-field behaviors to amygdaloid kindled convulsions in Wistar rats

Repeated low-intensity electrical stimulation (kindling) of the amygdala eventually produces convulsive behavior in animals. The present study examined the relationship between behaviors displayed in a novel open-field situation with behavioral characteristics of the kindled clonic convulsion (CC). Wistar rats were given two open-field tests and were subsequently kindled to clonic convulsions. A multiple regression analysis indicated that rats which urinated more often in the open-field tests tended to show longer latencies to CC onset. Thus, open-field urination was a significant predictor of latency to CC onset. It is suggested that an emotionality construct may be related to rate of kindling.     

Plasticity of the medial prefrontal cortex: Facilitated acquisition of intracranial self-stimulation by pretraining stimulation

Prior electrical stimulation of the medial prefrontal cortex MFC facilitated the subsequent acquisition of intracranial self-stimulation (ICSS) from the same MFC electrode site. Stimulations that were spaced over a period of six days were more effective in producing this facilitation than the same number of stimulations delivered over a two day period. These data suggest that the rewarding effects of MFC stimulation may involve some process akin to the kindling phenomenon and as such may provide insights in the neuronal modifications thought to underlie learning and memory.     

Hemispheric Prevalence Changes in Partial Epileptic Patients on Perceptual and Attentional Tasks

In relation to the general issue of the long-term effects of epileptic activity on the higher nervous functions, monohemispheric epileptic patients--divided into "lesional" [i.e., with computed tomography (CT) scan-visible lesions] and "nonlesional" (i.e., with CT scan-nonvisible lesions)--were submitted to dichotic verbal and tonal tasks, dichoptic verbal and spatial tasks, and a visual tachistoscopic attentional task. The aim was to investigate whether the typical patterns of hemispheric prevalence, which were observed in normal subjects by using these tests, undergo significant changes in epileptic patients. The findings versus normal subjects seem to demonstrate that (a) in lesional epileptic patients, the prevalence of the hemisphere without macroscopic lesions is a constant rule, whether or not this hemisphere is prevalent in normal subjects; (b) in nonlesional epileptic patients, the patterns are the following: when the epileptic hemisphere is the one that is prevalent in normal subjects, its prevalence is enhanced, whichever the hemisphere; when the epileptic hemisphere is not the hemisphere prevalent in normal subjects, the left one attracts and maintains prevalence, whereas the right one reduces and variously interferes with contralateral prevalence. It is concluded that, with respect to the functions tested, the nature of the epileptic foci seems to influence markedly the interhemispheric prevalence pattern.