Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
Neuropharmacology. 2011 Oct-Nov;61(5-6):1033-47. doi: 10.1016/j.neuropharm.2011.06.015. Epub 2011 Jun 29.
Epileptogenesis, i.e., the process leading to epilepsy, is a presumed consequence of brain insults including head trauma, stroke, infections, tumors, status epilepticus (SE), and complex febrile seizures. Typically, brain insults produce morphological and functional alterations in the hippocampal formation, including neurodegeneration in CA1, CA3, and, most consistently, the dentate hilus. Most of these alterations develop gradually, over several days, after the insult, providing a therapeutic window of opportunity for neuroprotective agents in the immediate post-injury period. We have previously reported that prolonged (four weeks) treatment with the antiepileptic drug valproate (VPA) after SE prevents hippocampal damage and most of the behavioral alterations that occur after brain insult, but not the development of spontaneously occurring seizures. These data indicated that VPA, although not preventing epilepsy, might be an effective disease-modifying treatment following brain insult. The present study was designed to (1) determine the therapeutic window for the neuroprotective effect of VPA after SE; (2) compare the efficacy of different intermittent i.p. versus continuous i.v. VPA treatment protocols; and (3) compare VPA with the glutamate (AMPA) receptor antagonist NS1209. As in our previous study with VPA, SE was induced by sustained electrical stimulation of the basolateral amygdala in rats and terminated after 4 h by diazepam. In vehicle controls, >90% of the animals developed significant neurodegeneration in the dentate hilus, whereas damage in CA1 and CA3 was more variable. Hilar parvalbumin-expressing interneurons were more sensitive to the effects of seizures than somatostatin-stained hilar interneurons or hilar mossy cells. Among the various VPA treatment protocols, continuous infusion of VPA for 24 immediately following the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage. Infusion with NS1209 for 24 h exhibited similar neuroprotective efficacy. These data demonstrate that short treatment after SE with either VPA or NS1209 is powerfully neuroprotective, and may be disease-modifying treatments following brain insult.
癫痫发生，即导致癫痫的过程，是脑损伤的一种假定后果，包括头部创伤、中风、感染、肿瘤、癫痫持续状态（SE）和复杂热性惊厥。通常情况下，脑损伤会导致海马结构的形态和功能改变，包括 CA1、CA3 以及最一致的齿状回的神经退行性变。这些改变大多在损伤后数天内逐渐发展，为损伤后即刻的神经保护剂提供了治疗机会窗口。我们之前曾报道，SE 后长时间（四周）使用抗癫痫药物丙戊酸钠（VPA）治疗可预防海马损伤和大多数脑损伤后发生的行为改变，但不能预防自发性发作的发生。这些数据表明，VPA 虽然不能预防癫痫，但可能是脑损伤后的一种有效的疾病修饰治疗方法。本研究旨在：（1）确定 SE 后 VPA 神经保护作用的治疗窗口；（2）比较不同间歇性 i.p.与连续 i.v. VPA 治疗方案的疗效；（3）比较 VPA 与谷氨酸（AMPA）受体拮抗剂 NS1209。与我们之前的 VPA 研究一样，SE 通过对大鼠基底外侧杏仁核的持续电刺激诱导，并在 4 小时后用地西泮终止。在载体对照组中，>90%的动物在齿状回出现明显的神经退行性变，而 CA1 和 CA3 的损伤则更为多变。棘状回表达的 parvalbumin 中间神经元比 somatostatin 染色的棘状回中间神经元或棘状回苔藓细胞对发作的影响更为敏感。在各种 VPA 治疗方案中，SE 后立即持续输注 VPA 24 小时是最有效的神经保护治疗方法，可预防大多数神经元损伤。连续输注 NS1209 24 小时具有相似的神经保护作用。这些数据表明，SE 后用 VPA 或 NS1209 进行短时间治疗具有强大的神经保护作用，可能是脑损伤后的疾病修饰治疗方法。
