Kupferberg H J
Preclinical Pharmacology Section Epilepsy Branch, National Institute of Neurological Diseases and Stroke, National Institute of Health, Bethesda, Maryland.
Pharm Weekbl Sci. 1992 Jun 19;14(3A):132-8. doi: 10.1007/BF01962704.
The identification of new anticonvulsant drugs depends on the use of different animal models of epilepsy. The models should be mechanism-independent, able to screen a large number of compounds, at limited cost and technical expertise. Primary screening models include genetic or reflex models of epilepsy and electrically and chemically induced seizures. Once active compounds have been identified, more advanced mechanistic and seizure-specific models are needed to refine the choice of a lead compound. These can be either in vivo or in vitro models. Models known to interact with specific receptors or the production of the putative neurotransmitters of neural excitability or inhibition are valuable in assessing possible mechanisms of action. In vitro models have evolved as important tools in correlating changes in electrical phenomena and therapeutic spectrum. The use of the hippocampal slice and the cultured neuron permits classification of anticonvulsant activity based on cellular actions of the drug. Interactions by the experimental drugs with specific subcellular fractions of the central nervous system augment information on possible mechanisms of action. The final choice of compounds for development requires synthesizing and comparing all of the pharmacodynamic information with the pharmacokinetic and toxicologic data. In the final analysis, no single animal model of epilepsy known today can assure the development of better drugs for all treatment of the epilepsies.
新型抗惊厥药物的鉴定依赖于使用不同的癫痫动物模型。这些模型应与机制无关，能够以有限的成本和技术专长筛选大量化合物。初级筛选模型包括癫痫的遗传或反射模型以及电诱导和化学诱导的癫痫发作。一旦确定了活性化合物，就需要更先进的机制性和癫痫发作特异性模型来优化先导化合物的选择。这些模型可以是体内模型或体外模型。已知与特定受体相互作用或与神经兴奋性或抑制的假定神经递质产生相关的模型，在评估可能的作用机制方面很有价值。体外模型已发展成为关联电现象变化和治疗谱的重要工具。使用海马切片和培养的神经元可以根据药物的细胞作用对抗惊厥活性进行分类。实验药物与中枢神经系统特定亚细胞部分的相互作用增加了关于可能作用机制的信息。用于开发的化合物的最终选择需要将所有药效学信息与药代动力学和毒理学数据进行综合和比较。归根结底，当今已知的任何单一癫痫动物模型都无法确保开发出适用于所有癫痫治疗的更好药物。
