Holtkamp M, Meierkord H
Department of Neurology, Charité - Universitätsmedizin Berlin (Campus Mitte), Charitéplatz 1, 10117, Berlin, Germany.
Cell Mol Life Sci. 2007 Aug;64(15):2023-41. doi: 10.1007/s00018-007-7021-2.
Pharmacological concepts tailored to status epilepticus, to epileptogenesis following acquired brain insults, and to ictogenesis in established epilepsy vary considerably and should ideally be directed at those pathophysiological mechanisms that presumably underly these conditions. Currently known important molecular targets include voltage-gated sodium and calcium channels, the gamma-aminobutyric acid (GABA) system and ionotropic glutamate receptors. Metabotropic glutamate receptors, potassium channels, and neurotransmitters such as acetylcholine, glycine, and monoamines are beyond the scope of this review. In status epilepticus, immediate failure of GABAergic inhibition occurs, and administration of benzodiazepines and barbiturates displays the pharmacostrategic mainstay. In epileptogenesis within limbic structures, the most important underlying pathophysiological mechanisms currently discussed are transient loss of inhibition and aberrant mossy fiber sprouting. Both processes may be facilitated by N-methy-D: -aspartat (NMDA) receptor regulation. NMDA antagonists may exhibit antiepileptogenic properties in experimental animals, but reliable data in humans are lacking. In established epilepsy, voltage-gated ion channels and impairment of GABAergic functions contribute to mechanisms facilitating ictogenesis. Blockade of sodium and calcium channels and enhancement of GABAergic inhibition are currently the most important tools to prevent the occurrence of seizures.
针对癫痫持续状态、获得性脑损伤后的癫痫发生以及已确诊癫痫中的发作形成的药理学概念差异很大,理想情况下应针对可能是这些病症基础的病理生理机制。目前已知的重要分子靶点包括电压门控钠通道和钙通道、γ-氨基丁酸(GABA)系统和离子型谷氨酸受体。代谢型谷氨酸受体、钾通道以及乙酰胆碱、甘氨酸和单胺等神经递质不在本综述范围内。在癫痫持续状态中,GABA能抑制立即失效,苯二氮䓬类药物和巴比妥类药物的给药是主要的药物策略。在边缘结构的癫痫发生中,目前讨论的最重要的潜在病理生理机制是抑制的短暂丧失和异常的苔藓纤维发芽。这两个过程都可能通过N-甲基-D-天冬氨酸(NMDA)受体调节而得到促进。NMDA拮抗剂在实验动物中可能具有抗癫痫发生特性,但缺乏在人体中的可靠数据。在已确诊的癫痫中,电压门控离子通道和GABA能功能受损有助于发作形成机制。阻断钠通道和钙通道以及增强GABA能抑制是目前预防癫痫发作的最重要手段。