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当前的抗癫痫药物无效。这些病人是 由于多种药物治疗和药物剂量大，经常受到严重不良反应的影响；因此， 显然需要有效的治疗方法来改善患者的生活质量。更好的发现 治疗一直滞后，因为缺乏经过验证的动物模型来更接近地概括 人类的致痫状态。基于对脑瘫患者手术切除的海马区组织的研究 在医学上难治性颞叶癫痫(TIE)，我们提出了一种新的TLE大鼠模型，通过慢性， 谷氨酰胺合成酶拮抗剂蛋氨酸亚硫胺(MSO)脑内输注。这款车 复制了人类TLE病理的一个显著特征，即谷氨酰胺合成酶缺乏 在海马体中。初步结果表明，接受MSO治疗的动物会出现反复发作。 以及人类疾病的几个神经病理特征。该提案旨在进一步验证 该模型作为未来测试新的治疗方法的前奏。以下功能将包括 确认：(1)颅内脑电记录将寻求确认癫痫发作的近侧颞部起源，并 提供有关其他重要癫痫参数的信息。(2)神经组织学研究将尝试绘制 并量化对海马体和其他脑区的有限损害。(3)体内微透析 研究将确定致痫患者细胞外谷氨酸水平是否升高。 海马体，和人类的TLE一样。 与公共卫生相关：近80万美国癫痫患者癫痫发作不受控制 不能用目前可用的药物治疗。因此，需要更有效的癫痫治疗方法。 这项提议试图验证一种新的动物模型，这种模型可能会极大地加快寻找更好的动物 治疗这种疾病的方法。

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.