Antiepileptogenic & Disease Modifying Effects of AEDs

抗癫痫原

• 批准号: 6931937
• 负责人: ASLA SL PITKANEN
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF KUOPIO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-03 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931937
• 关键词: amygdala; anticonvulsants; behavior test; brain disorder chemotherapy; brain electrical activity; carbamazepine; chemoprevention; cognition; disease /disorder prevention /control; drug administration rate /duration; drug screening /evaluation; electroencephalography; epilepsy; hippocampus; histopathology; laboratory rat; learning; neuropathology; neuroprotectants; nonhuman therapy evaluation; valproate

DESCRIPTION (provided by applicant): Each year about 140,000 Americans and 280,000 Europeans are diagnosed with epilepsy. Epidemiological studies suggest that symptomatic and presumed symptomatic etiologies comprise about 60% of the cases. These data suggest that about 250,000 individuals undergo epileptogenesis each year in the two continents. Even though the elevated risk of epileptogenesis after epileptogenic insult like head trauma, stroke, or status epilepticus (SE) is readily identifiable, there is no evidence-based treatment that can be offered to patients at risk of epileptogenesis. Aim of the present study is to investigate whether administration of 3 standard antiepileptic drugs (carbamazepine, valproate, levetiracetam) as monotherapy during epileptogenic phase (1) prevents the development of epilepsy, and if not, (2) has a disease modifying effect. The compounds were chosen based on their different mechanism of action and variable effects on the development of kindling, a model considered to predict the antiepileptogenic effects in humans. To mimic clinical situation, administration of compounds (carbamazepine 120 mg/kg/d, valproate 600 mg/kg/d, levetiracetam 150 mg/kg/d, or vehicle) will be started 24 h after the beginning of SE (SE is stopped at 4 h with diazepam) induced by electrical stimulation of the amygdala in adult male Sprague-Dawley rats (n=10-20 per group). Treatment will be continued for 1 wk that corresponds to 20-25% of the latency period. The first 2-wk continuous video-EEG monitoring will be started 10 wk after SE. To confirm antiepileptogenesis or disease modification, the second 2-wk continuous video-EEG will be started 14 wk after SE. Thereafter, animals will undergo behavioral testing (Morris water-maze and fear-conditioning). Finally, animals will be perfused for histology. As outcome measures we use (1) development of epilepsy (yes/no), (2) severity of epilepsy (frequency, duration, behavioral severity of seizures), (3) spatial and emotional learning and memory, and (4) pathology (cell death, mossy fiber sprouting).

描述（由申请人提供）：每年约有14万美国人和280,000名欧洲人被诊断出患有癫痫病。 流行病学研究表明，有症状和假定的症状病因占病例的60％。 这些数据表明，大约25万个人每年在两个大洲进行癫痫发生。 即使癫痫发生后的癫痫发生风险升高，例如头部外伤，中风或癫痫持续状态（SE），但尚无循证治疗，可以提供给有癫痫生成风险的患者。 本研究的目的是研究在癫痫剂阶段（1）在癫痫发育中施用3种标准抗癫痫药（卡马西平，丙丙酸酯，黎乙酰氨酸）是否具有癫痫发育，如果没有，（2）具有疾病改变作用。 这些化合物是根据其不同的作用机理和对点燃发育的可变作用选择的，该模型被认为是预测人类抗癫痫发作的作用。 在模仿临床状况下，将在SE开始后24小时开始服用化合物（卡马西平120 mg/kg/kg/kg/kg/kg/d，丙戊酸600 mg/kg/d，levetiracetam 150 mg/kg/d或载体）。 （n =每组10-20）。 将继续进行1周的治疗，对应于潜伏期的20-25％。 SE之后，第一个2周连续的视频EEG监视将开始10周。 为了确认抗癫痫发生或疾病的修饰，第二个2-WK连续视频EEG将在SE之后开始14周。 此后，动物将经过行为测试（莫里斯水迷宫和恐惧调节）。 最后，动物将被灌注于组织学。 作为结果度量，我们使用（1）癫痫发育（是/否），（2）癫痫的严重程度（频率，持续时间，癫痫发作的行为严重程度），（3）空间和情感学习和记忆，以及（4）病理学（细胞死亡，苔藓纤维芽）。

项目成果

Therapeutic approaches to epileptogenesis--hope on the horizon.

• DOI: 10.1111/j.1528-1167.2010.02602.x
• 发表时间: 2010-07
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Pitkänen A