Evaluation of models of pharmacoresistant epilepsy.

耐药性癫痫模型的评估。

• 批准号: 6931486
• 负责人: H Steve WHITE
• 金额: $ 17.29万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-02 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931486
• 关键词: anticonvulsants; brain disorder chemotherapy; chronic disease /disorder; disease /disorder model; dosage; drug screening /evaluation; electrophysiology; entorhinal cortex; epilepsy; generalized seizures; hippocampus; information systems; kainate; kindling; laboratory rat; model design /development; multidrug resistance; neuropharmacology; nonhuman therapy evaluation; partial seizure; sectioning; temporal lobe /cortex disorder; tissue /cell preparation

DESCRIPTION (provided by applicant): Despite recent advances in the treatment of epilepsy, more than 35-40% of the 2.5 million Americans receiving antiepileptic drugs (AED) remain refractory to existing AED therapies. In order to better understand the etiology of pharmacorestance to AED and to facilitate the development of innovative therapeutic approaches for the management of pharmacoresistant epilepsy, there is a great need to validate and systematically characterize drug effects in both in vivo and in vitro animal models that display persistent seizure activity (or seizure-like activity in vitro) which is refractory or responds poorly to at least two differentially acting AED at maximal tolerated doses. The goal of the current proposal is therefore to test the hypothesis that "the 'entorhinal-hippocampal slice' and the "lamotrigine (LTG)-resistant kindled rat' models are pharmacoresistant to established antiepileptic drugs and that AED found effective in one or both of these models would be novel relative to the currently available AED." This hypothesis will be tested by utilizing a two-tiered approach wherein the effects of multiple standard and investigational AED will be assessed according to the following two Specific Aims. Specific Aim 1 will evaluate the ability of a battery of mechanistically distinct established and investigational AED to eliminate spontaneous, electrographic seizure-like activity recorded in the medial entorhinal cortex in brain slices obtained from animals treated with kainic acid (KA). Specific Aim 2 will evaluate the ability of a battery of mechanistically distinct established and investigational AED to suppress focal and generalized seizures in LTG-resistant amygdala-kindled rats. Dose-response relationships will be determined in vitro for at least thirteen different "standard" and "investigational" AED therapies: phenytoin, carbamazepine, valproate, ethosuxamide, vigabatrin, topiramate, lamotrigine, felbamate, levetiracetam, harkoseride, tiagabine, valrocemide, and retigabine. Furthermore, these drugs will be evaluated in vivo for their ability to inhibit focal and generalized seizure activity in both the traditional and lamotrigine-resistant amygdala kindled rat models of temporal lobe epilepsy. These experiments will establish a comparative database for traditional and nontraditional AED in both in vitro and in vivo models, provide insight towards the predictive value of pharmacoresistance observed with in vitro screening paradigms for identifying pharmacoresistance observed with in vivo models of pharmacoresistant epilepsy, and set the stage for the development of future therapeutic interventions for the treatment of pharmacoresistant epilepsy.

描述（由申请人提供）：尽管最近在癫痫治疗方面取得了进展，但在接受抗癫痫药物 (AED) 的 250 万美国人中，超过 35-40% 的人仍然对现有的 AED 疗法无效。为了更好地了解 AED 耐药性的病因，并促进开发治疗耐药性癫痫的创新治疗方法，非常需要在体内和体外动物模型中验证和系统地表征药物作用，这些模型显示持续性癫痫发作（或体外类似癫痫发作的活动），在最大耐受剂量下对至少两种作用不同的 AED 具有难治性或反应​​不佳。因此，当前提案的目标是检验以下假设：“‘内嗅-海马切片’和‘拉莫三嗪 (LTG) 耐药点燃大鼠’模型对现有的抗癫痫药物具有耐药性，并且 AED 对以下一种或两种情况有效：这些模型相对于目前可用的 AED 来说将是新颖的。”该假设将通过利用两层方法进行测试，其中将根据以下两个具体方法评估多种标准和研究性 AED 的效果目标：特定目标 1 将评估一系列机制独特的已建立和研究中的 AED 消除在用红藻氨酸 (KA) 治疗的动物脑切片中记录的内侧内嗅皮层中记录的自发性癫痫样活动的能力。 2 将评估一系列机制不同的已建立和研究中的 AED 抑制 LTG 抗性杏仁核点燃大鼠的局灶性和全身性癫痫发作的能力。将在体外确定至少 13 种不同“标准”和“研究性”AED 疗法的剂量-反应关系：苯妥英、卡马西平、丙戊酸盐、乙舒酰胺、氨己烯酸、托吡酯、拉莫三嗪、非氨酯、左乙拉西坦、哈考塞利、噻加宾、丙罗塞米和瑞替加滨。此外，将在体内评估这些药物在传统的和拉莫三嗪耐药的杏仁核点燃的颞叶癫痫大鼠模型中抑制局灶性和全身性癫痫活动的能力。这些实验将在体外和体内模型中建立传统和非传统 AED 的比较数据库，深入了解体外筛选范式观察到的药物耐药性的预测价值，以识别耐药性癫痫体内模型观察到的药物耐药性，并设定开发未来治疗耐药性癫痫的治疗干预措施的阶段。