Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs.: A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy
Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs.: A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy
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DOI：
10.1016/s0920-1211(02)00073-6
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发表时间：
2002-06-01
影响因子：
2.2
通讯作者：
Löscher, W
中科院分区：
文献类型：
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作者：
Löscher, W
癫痫的控制主要集中在癫痫发作后使用抗癫痫药物（AED）抑制癫痫发作。 AED 极大地改善了癫痫患者的生活。然而，目前的临床和实验数据并不支持认为 AED 除了抑制癫痫发作之外，还能改变潜在的癫痫发生过程，从而改变疾病的病程及其预后。一种有趣的可能性是通过预防癫痫发生（大脑发生癫痫的过程）来控制获得性癫痫。许多 AED 已在临床试验中进行了评估，以测试它们是否可以预防人类癫痫的发生，但迄今为止，还没有药物在此类试验中被证明是有效的。因此，迫切需要真正具有抗癫痫作用的药物来预防癫痫或改变其自然病程。为此，癫痫动物模型是重要的先决条件。有多种患有慢性脑功能障碍的动物模型被认为反映了人类癫痫的潜在过程。此类癫痫的慢性模型包括颞叶癫痫(TLE)的点燃模型、TLE的癫痫持续状态模型(其中癫痫在持续癫痫持续状态之后发展)以及不同类型癫痫的遗传模型。目前，点燃模型和状态后模型，例如毛果芸香碱或红藻氨酸模型，是研究癫痫发生过程和预防或改变癫痫的药物靶点最广泛使用的模型。此外，这些模型中的癫痫发作可用于测试抗癫痫药物的作用。慢性模型的药理学与先前健康（非癫痫）动物的急性（反应性或诱发性）癫痫发作模型（例如最大电击癫痫发作试验）的比较表明，慢性癫痫模型的药物测试产生的数据更能预测临床疗效和不良反应，因此慢性模型应在药物开发中相对较早地使用，以尽量减少假阳性。有趣的是，完全点燃的大鼠中引发的点燃性癫痫发作和状态后模型中的自发性复发性癫痫发作的药理学非常相似。然而，当这些模型用于研究药物的抗癫痫作用时，模型之间存在显着差异，表明不同模型之间甚至不同 TLE 状态后模型之间癫痫发生的过程也不同。 TLE 模型临床验证的一个问题是缺乏有效预防人类癫痫的 AED。因此，目前不可能判断哪种慢性模型最适合开发寻找抗癫痫药物和缓解疾病药物的新策略，而是应该使用一系列模型来避免假阴性或阳性预测。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Control of epilepsy has primarily focused on suppressing seizure activity by antiepileptic drugs (AEDs) after epilepsy has developed. AEDs have greatly improved the lives of people with epilepsy. However, the belief that AEDs, in addition to suppressing seizures, alter the underlying epileptogenic process and, in doing so, the course of the disease and its prognosis, is not supported by the current clinical and experimental data. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. A number of AEDs have been evaluated in clinical trials to test whether they prevent epileptogenesis in humans, but to date no drug has been shown to be effective in such trials. Thus, there is a pressing need for drugs that are truly antiepileptogenic to either prevent epilepsy or alter its natural course. For this purpose, animal models of epilepsy are an important prerequisite. There are various animal models with chronic brain dysfunctions thought to reflect the processes underlying human epilepsy. Such chronic models of epilepsy include the kindling model of temporal lobe epilepsy (TLE), post-status epilepticus models of TLE in which epilepsy develops after a sustained status epilepticus, and genetic models of different types of epilepsy. Currently, the kindling model and post-status models, such as the pilocarpine or kainate models, are the most widely used models for studies on epileptogenic processes and on drug targets by which epilepsy can be prevented or modified. Furthermore, the seizures in these models can be used for testing of antiepileptic drug effects. A comparison of the pharmacology of chronic models with models of acute (reactive or provoked) seizures in previously healthy (non-epileptic) animals, such as the maximal electroshock seizure test, demonstrates that drug testing in chronic models of epilepsy yields data which are more predictive of clinical efficacy and adverse effects, so that chronic models should be used relatively early in drug development to minimize false positives. Interestingly, the pharmacology of elicited kindled seizures in fully kindled rats and spontaneous recurrent seizures in post-status models is remarkably similar. However, when these models are used for studying the antiepileptogenic effects of drugs, marked differences between models exist, indicating that the processes underlying epileptogenesis differ among models, even among different post-status models of TLE. A problem for clinical validation of TLE models is the lack of an AED, which effectively prevents epilepsy in humans. Thus, at present, it is not possible to judge which chronic model is best suited for developing new strategies in the search for antiepileptogenic and disease-modifying drugs, but rather a battery of models should be used to avoid false negative or positive predictions. (C) 2002 Elsevier Science B.V. All rights reserved.