Temporal lobe epilepsy - validation of a new animal model

描述（由申请人提供）：近三分之一的癫痫患者对目前的抗癫痫药物难以治愈。这些患者由于多药治疗、用药剂量大，往往出现明显的不良反应；因此，显然需要更有效的治疗方法来改善患者的生活质量。由于缺乏更接近地概括人类癫痫发病状态的有效动物模型，更好的治疗方法的发现一直滞后。基于对难治性颞叶癫痫（TIE）患者手术切除海马组织的研究，我们提出了一种通过慢性脑内输注谷氨酰胺合成酶拮抗剂甲硫氨酸亚砜胺（MSO）的新型颞叶癫痫大鼠模型。该模型再现了人类TLE病理的一个突出特征，即海马中谷氨酰胺合成酶的缺乏。初步结果表明，mso治疗的动物出现复发性癫痫发作和人类疾病的一些神经病理特征。该建议旨在进一步验证该模型，作为未来测试新治疗方法的前奏。以下特征将被验证：(1)颅内脑电图记录将寻求确认癫痫发作的内侧颞起源，并提供其他重要癫痫发作参数的信息。(2)神经组织学研究将尝试绘制和量化对海马体和其他大脑区域的有限损伤。(3)体内微透析研究将确定癫痫性海马细胞外谷氨酸水平是否升高，如人类TLE。与公共卫生的相关性：近80万美国癫痫患者患有无法控制的癫痫发作，目前可用的药物无法治疗。因此，需要更有效的癫痫治疗方法。这项提议旨在验证一种新的动物模型，这种模型可能会大大加快寻找更好的治疗这种疾病的方法。

DESCRIPTION (provided by applicant): Nearly one third of all patients with epilepsy are refractory to current antiepileptic drugs. These patients are often affected by significant adverse effects due to multi-drug treatment and high drug dosage; thus, more efficacious therapies that will improve the patient's quality of life are clearly needed. The discovery of better therapies has been lagging due to a lack of validated animal models that more closely recapitulate the human epileptogenic state. Based on studies of surgically resected hippocampal tissue from patients with medically intractable temporal lobe epilepsy (TIE), we propose here a novel rat model of TLE by chronic, intracerebral infusions of the glutamine synthetase antagonist, methionine sulfoximine (MSO). This model reproduces a prominent feature of the pathology of human TLE, namely a deficiency of glutamine synthetase in the hippocampus. Preliminary results indicate that the MSO-treated animals develop recurrent seizures and several neuropathological characteristics of the human disease. This proposal seeks to further validate the model as a prelude for future testing of novel therapeutic approaches. The following features will be validated: (1) Intracranial EEG recordings will seek to confirm the mesial temporal origin of the seizures and provide information on other important seizure parameters. (2) Neurohistological studies will attempt to map and quantitate the limited damage to the hippocampus and other brain areas. (3) In vivo microdialysis studies will determine whether extracellular levels of glutamate are elevated in the epileptogenic hippocampus, as in human TLE. Relevance to public health: Nearly 800,000 Americans with epilepsy suffer from uncontrolled seizures that cannot be treated with currently available drugs. More effective therapies of epilepsy are therefore needed. This proposal seeks to validate a new animal model that may greatly speed up the search for better therapies against this disorder.