Ferland R J, Applegate C D
Department of Neurology, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Epilepsy Res. 1998 Mar;30(1):49-62. doi: 10.1016/s0920-1211(97)00093-4.
We recently have described a novel model of epileptogenesis utilizing the inhalant chemoconvulsant, flurothyl (Applegate et al., 1997; Samoriski and Applegate, 1997). The hallmark feature of this model is a change in behavioral seizure phenotype from a forebrain seizure, observed during the initial flurothyl exposures, to a brainstem seizure, elicited by flurothyl, after a 28-day stimulation free incubation period. In this study, we sought to establish the basis for this change in behavioral seizure response. To this end, we examined the effects of exposure to this paradigm on the generalized brainstem seizure threshold and on the propagation of forebrain seizures onto the brainstem seizure substrate. Ten mice were given flurothyl-induced generalized forebrain seizures on 8 consecutive days (induction phase). The other ten mice were not exposed to the flurothyl induction paradigm and served as controls. Minimal corneal electroconvulsive shock (mECS--20 mA) was used to assay whether there was any change in the animals' generalized brainstem seizure thresholds at 3, 14 and 28 days following the last flurothyl seizure trial. Mice that were exposed to flurothyl exhibited a progressive increase in the percentage of animals having a mECS-induced brainstem seizure when tested at 3 (40%), 14 (70%) and 28 (90%) days following the last flurothyl seizure. Control mice rarely had a brainstem seizure at any of the three time points tested, mostly forebrain seizures were observed. These results suggest that there is a significant progressive lowering of the brainstem seizure threshold, during the incubation phase of the flurothyl paradigm, which is coincident with the previously reported time course of change in the behavioral seizure phenotype observed using this flurothyl model (Applegate et al., 1997; Samoriski and Applegate, 1997). Following mECS testing, mice were implanted with bipolar electrodes and kindled from the olfactory bulb (OB). Mice exposed to the flurothyl paradigm demonstrated significantly faster kindling rates, longer afterdischarge durations. and longer durations of and latencies to stage 5 seizures compared to controls. Furthermore, animals exposed to the flurothyl protocol demonstrated an increase in the expression of brainstem seizures after focally-elicited OB afterdischarges. These results suggest that there is an increased interaction between the forebrain and brainstem seizure systems after exposure to this model of epileptogenesis. Together, results indicate that the change in behavioral seizure phenotype observed following exposure to our flurothyl paradigm are promoted by both decreases in brainstem seizure thresholds and facilitated forebrain seizure propagation onto the brainstem seizure system.
我们最近描述了一种利用吸入性化学惊厥剂氟代乙酰胺建立的癫痫发生新模型（阿普尔盖特等人，1997年；萨莫里斯基和阿普尔盖特，1997年）。该模型的标志性特征是行为性癫痫发作表型发生变化，从最初接触氟代乙酰胺期间观察到的前脑癫痫发作，转变为在28天无刺激孵育期后由氟代乙酰胺诱发的脑干癫痫发作。在本研究中，我们试图确定这种行为性癫痫发作反应变化的基础。为此，我们研究了暴露于该范式对全身性脑干癫痫发作阈值以及前脑癫痫发作向脑干癫痫发作底物传播的影响。十只小鼠连续8天接受氟代乙酰胺诱发的全身性前脑癫痫发作（诱导期）。另外十只小鼠未暴露于氟代乙酰胺诱导范式，作为对照。使用最小角膜电惊厥休克（mECS - 20 mA）来测定在最后一次氟代乙酰胺癫痫发作试验后的3天、14天和28天，动物的全身性脑干癫痫发作阈值是否有任何变化。暴露于氟代乙酰胺的小鼠在最后一次氟代乙酰胺癫痫发作后的3天（40%）、14天（70%）和28天（90%）进行测试时，出现mECS诱发脑干癫痫发作的动物百分比逐渐增加。对照小鼠在测试的三个时间点中很少出现脑干癫痫发作，大多观察到前脑癫痫发作。这些结果表明，在氟代乙酰胺范式的孵育期，脑干癫痫发作阈值显著逐渐降低，这与之前使用该氟代乙酰胺模型观察到的行为性癫痫发作表型变化的时间进程一致（阿普尔盖特等人，1997年；萨莫里斯基和阿普尔盖特，1997年）。在mECS测试后，小鼠植入双极电极并从嗅球（OB）进行点燃。与对照组相比，暴露于氟代乙酰胺范式的小鼠表现出明显更快的点燃率、更长的后放电持续时间，以及到5期癫痫发作的持续时间和潜伏期更长。此外，暴露于氟代乙酰胺方案的动物在局灶性诱发OB后放电后，脑干癫痫发作的表达增加。这些结果表明，暴露于这种癫痫发生模型后，前脑和脑干癫痫发作系统之间的相互作用增加。总之，结果表明，暴露于我们的氟代乙酰胺范式后观察到的行为性癫痫发作表型变化，是由脑干癫痫发作阈值降低以及前脑癫痫发作向脑干癫痫发作系统的传播促进所致。
