Heinemann U, Draguhn A, Ficker E, Stabel J, Zhang C L
Institut für Physiologie der Charité, Humboldt Universität, Berlin, Germany.
Epilepsia. 1994;35 Suppl 5:S10-21. doi: 10.1111/j.1528-1157.1994.tb05959.x.
Presently, most strategies for development of antiepileptic drugs (AEDs) center around seizure models that are known to respond to presently marketed AEDs. These strategies do not take into account that epilepsy can be a progressive disease. Moreover, region-specific aspects of epileptogenesis are rarely considered when new AEDs are developed. Seizures in the temporal lobe are often difficult to treat. Animal studies on various seizure models in the hippocampus and the entorhinal cortex (EC) suggest that these structures do not a priori produce seizures that are difficult to treat. However, seizure-like events in the EC tend to progress to a state of status epilepticus-like activity that cannot be suppressed by presently marketed AEDs. Loss of gamma-aminobutyric acid (GABA)ergic neurotransmission and increased excitatory synaptic coupling seem to cooperate for induction of this state. Epilepsy induced alterations in the interaction between the EC and the hippocampus may lead to alterations that facilitate precipitation of seizures. Because of the recurrent interaction between the hippocampus and the EC, these seizures may reach an intensity that is no longer controllable by presently available AEDs. Ontogenetic alterations of the circuitry between the EC and the hippocampus, seizure-induced stabilization of synaptic connections overexpressed during ontogenesis, seizure-induced lesions and subsequent rearrangements of internal cell properties, and synaptic arrangements and kindling-like alterations of nerve cell and glial behavior may all be involved in the generation of a neuronal aggregate whose balance between inhibitory and excitatory processes becomes readily disturbed. Strategies for the development of AEDs treating such seizures should suppress hyperactivity and prevent progression of epileptogenesis. AEDs directed against seizures may be effective if they can be given in sufficient concentrations to suppress very intense local seizures.
目前，大多数抗癫痫药物（AEDs）的研发策略都围绕着已知对现有上市AEDs有反应的癫痫模型展开。这些策略没有考虑到癫痫可能是一种进行性疾病。此外，在开发新的AEDs时，很少考虑癫痫发生的区域特异性方面。颞叶癫痫往往难以治疗。对海马体和内嗅皮质（EC）各种癫痫模型的动物研究表明，这些结构并非先验地产生难以治疗的癫痫发作。然而，EC中的癫痫样事件往往会发展为一种癫痫持续状态样活动，目前上市的AEDs无法抑制这种活动。γ-氨基丁酸（GABA）能神经传递的丧失和兴奋性突触耦合的增加似乎共同促成了这种状态的诱导。癫痫诱导的EC与海马体之间相互作用的改变可能导致促进癫痫发作的改变。由于海马体和EC之间的反复相互作用，这些癫痫发作可能会达到目前可用AEDs无法控制的强度。EC与海马体之间神经回路的个体发育改变、癫痫发作诱导的在个体发育过程中过度表达的突触连接的稳定、癫痫发作诱导的损伤以及随后内部细胞特性的重新排列，以及神经细胞和胶质细胞行为的突触排列和点燃样改变，都可能参与了一个神经元聚集体的产生，其抑制和兴奋过程之间的平衡很容易被打乱。治疗此类癫痫发作的AEDs研发策略应抑制过度活动并防止癫痫发生的进展。如果能够以足够的浓度给药以抑制非常强烈的局部癫痫发作，针对癫痫发作的AEDs可能会有效。
