Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
Department of Anatomy and Cell Biology, Indiana University/Purdue University, Indianapolis, IN, USA.
Brain Res. 2019 Nov 1;1722:146356. doi: 10.1016/j.brainres.2019.146356. Epub 2019 Jul 29.
The need for improved antiepileptics is clearly mandated despite the existence of multiple existing medicines from different chemical and mechanistic classes. Standard of care agents do not fully control epilepsies and have a variety of side-effect and safety issues. Patients typically take multiple antiepileptic drugs and yet many continue to have seizures. Antiepileptic-unresponsive seizures are life-disrupting and life-threatening. One approach to seizure control is surgical resection of affected brain tissue and associated neural circuits. Although non-human brain studies can provide insight into novel antiepileptic mechanisms, human epileptic brain is the bottom-line biological substrate. Human epileptic brain can provide definitive information on the presence or absence of the putative protein targets of interest in the patient population, the potential changes in these proteins in the epileptic state, and the engagement of novel molecules and their functional impact in target tissue. In this review, we discuss data on two novel potential antiepileptic drugs. CERC-611 (LY3130481) is an AMPA receptor antagonist that selectively blocks AMPA receptors associated with the auxiliary protein TARP γ-8 and is in clinical development. KRM-II-81 is a positive allosteric modulator of GABA receptors selectively associated with protein subunits α2 and α 3. Preclinical data on these compounds argue that patient-based biological data increase the probability that a newly discovered molecule will translate its antiepileptic potential to patients.
尽管存在多种来自不同化学和机制类别的现有药物，但显然需要改进抗癫痫药。标准治疗药物不能完全控制癫痫，并且存在各种副作用和安全问题。患者通常需要服用多种抗癫痫药物，但许多患者仍会发作。抗癫痫药物无反应性发作会扰乱生活并危及生命。一种控制癫痫发作的方法是切除受影响的脑组织和相关的神经回路。虽然非人类大脑研究可以提供对新的抗癫痫机制的深入了解，但人类癫痫大脑是最终的生物基底。人类癫痫大脑可以提供关于感兴趣的假定蛋白质靶标在患者群体中的存在或不存在、这些蛋白质在癫痫状态下的潜在变化以及新型分子的参与及其在靶组织中的功能影响的明确信息。在这篇综述中，我们讨论了两种新型潜在抗癫痫药物的数据。CERC-611（LY3130481）是一种 AMPA 受体拮抗剂，选择性阻断与辅助蛋白 TARP γ-8 相关的 AMPA 受体，目前正在临床开发中。KRM-II-81 是一种 GABA 受体的正变构调节剂，选择性地与蛋白亚基 α2 和 α3 相关。这些化合物的临床前数据表明，基于患者的生物学数据增加了新发现的分子将其抗癫痫潜力转化为患者的可能性。
