Temporal lobe epilepsy - validation of a new animal model

颞叶癫痫：一种新动物模型的验证 近三分之一的癫痫患者对目前的抗癫痫药物难治。这些患者 由于多种药物治疗和高药物剂量，经常受到显著不良反应的影响;因此， 显然需要改善患者生活质量的有效疗法。更好的发现 由于缺乏经过验证的动物模型， 人类癫痫状态基于对手术切除的海马组织的研究， 药物难治性颞叶癫痫（TIE），我们在这里提出了一种新的TLE大鼠模型， 脑内输注谷氨酰胺合成酶拮抗剂甲硫氨酸亚砜亚胺（MSO）。该模型 再现了人TLE病理学的显著特征，即谷氨酰胺合成酶缺乏 在海马区。初步结果表明，MSO处理的动物出现反复发作， 以及人类疾病的几个神经病理学特征。该提案旨在进一步验证 该模型作为未来测试新治疗方法的前奏。以下功能将 经验证：（1）颅内EEG记录将寻求确认癫痫发作的内侧颞叶起源， 提供关于其他重要癫痫参数的信息。(2)神经组织学研究将试图绘制 并对海马体和其他大脑区域的有限损伤进行定量。(3)体内微透析 研究将确定在致痫性癫痫中细胞外谷氨酸水平是否升高， 海马体，如人类TLE。 与公共卫生的相关性：近80万美国癫痫患者患有不受控制的癫痫发作， 不能用现有的药物治疗。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，这可能会大大加快寻找更好的 治疗这种疾病。

Temporal lobe epilepsy: validation of a new animal model 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 therfore needed. This proposal seeks to validate a new animal model that may greatly speed up the search for better therapies against this disorder.