目的:鉴于其影响线粒体的关键稳态作用,离子型和代谢型受体,和电压门控离子通道,sigma-1受体(Sig1R)代表了癫痫治疗的一个有趣的目标。在急性癫痫发作模型中已经报道了正变构调节剂E1R的抗癫痫作用。虽然5-羟色胺能神经传递的调节被认为是芬氟拉明的主要作用机制,它与Sig1R的相互作用可能有额外的相关性。
方法:为了进一步探索Sig1R作为靶标的潜力,我们评估了E1R和芬氟拉明在两种慢性小鼠模型中的疗效和耐受性,包括杏仁核点燃范例和海马内海藻酸盐模型。使用与Sig1R拮抗剂NE-100的组合实验分析与Sig1R的相互作用的相对贡献。
结果:而E1R在完全点燃的小鼠中以良好的耐受剂量发挥明显的剂量依赖性抗癫痫作用,仅观察到对芬氟拉明的反应有限,没有明显的剂量依赖性。在海马内海藻酸盐模型中,E1R未能影响电图癫痫发作活动。相比之下,芬氟拉明显着降低了心电图发作事件的频率及其累积持续时间。NE-100预处理降低了E1R和芬氟拉明在点燃模型中的作用。令人惊讶的是,在海马内红藻氨酸模型中,暴露于NE-100之前会增强和延长芬氟拉明的抗癫痫作用。
结论:结论:引燃数据进一步支持Sig1R作为新型抗癫痫药物的有趣靶标.然而,有必要进一步探讨E1R在伴有自发性癫痫发作的慢性癫痫模型中的临床前表现。尽管点燃范式的影响相当有限,海马内海藻酸盐模型的研究结果表明,进一步评估芬氟拉明可能的广谱潜力是有意义的.
OBJECTIVE: Given its key homeostatic role affecting mitochondria, ionotropic and metabotropic receptors, and voltage-gated ion channels, sigma-1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. Although modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance.
METHODS: To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE-100.
RESULTS: Whereas E1R exerted pronounced dose-dependent antiseizure effects at well-tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine, without a clear dose dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE-100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre-exposure to NE-100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine\'s antiseizure effects.
CONCLUSIONS: In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad-spectrum potential of fenfluramine.