Yip Ka Lai, Zhou Cilla, Anderson Lyndsey L, Hawkins Nicole A, Kearney Jennifer A, Arnold Jonathon C
Discipline of Pharmacology, Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, NSW 2050, Australia; Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, NSW 2050, Australia; Brain and Mind Centre, The University of Sydney, NSW 2050, Australia.
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, IL 60611, USA.
Prostaglandins Other Lipid Mediat. 2025 Jan;176:106943. doi: 10.1016/j.prostaglandins.2024.106943. Epub 2024 Dec 17.
Dravet syndrome is a severe, intractable epilepsy in which 80 % of patients have a de novo mutation in the gene SCN1A. We recently reported that a high seizure burden increased hippocampal concentrations of an array of pro-inflammatory prostaglandins in the Scn1a mouse model of Dravet syndrome. This raised the possibility that a high seizure burden might also trigger the accumulation of specialized pro-resolving mediators that facilitate the resolution of neuroinflammation and brain repair. The present study therefore aimed to examine whether a high seizure burden increased hippocampal concentrations of various specialized pro-resolving mediators in the Scn1a mouse model of Dravet syndrome.
Scn1a mice at postnatal day 21 (P21) were primed with a single hyperthermia-induced seizure event to induce a high seizure burden. On P24 primed Scn1a mice with a high seizure burden, unprimed naïve Scn1a mice and wild-type (WT) mice were euthanized and hippocampal tissue was collected for analysis of various specialized pro-resolving mediators using liquid chromatography mass spectrometry.
Scn1a mice with a high seizure burden showed increased hippocampal concentrations of the pro-inflammatory leukotrienes B4 and E4. Further, a high seizure burden increased hippocampal concentrations of various special pro-resolving mediators, including the maresins (maresin1), D-series resolvins (RVD1 and RVD4), and protectin (PCTR1). To further characterize these changes, we determined the mRNA expression of lipoxygenase genes, as these synthetic enzymes are common across classes of specialized pro-resolving mediators. However, hippocampal expression of Alox5, Alox12 and Alox15 were not influenced by a high seizure burden.
We report for the first time that a high seizure burden increases the hippocampal concentrations of various specialized pro-resolving mediators in Scn1a mice. This provides a platform for future studies to examine whether modulation of these mediators might be exploited to reduce seizures and facilitate brain repair in intractable epilepsy syndromes.
德雷维特综合征是一种严重的难治性癫痫，其中80%的患者基因SCN1A存在新生突变。我们最近报道，在德雷维特综合征的Scn1a小鼠模型中，高癫痫发作负荷会增加一系列促炎前列腺素在海马中的浓度。这就提出了一种可能性，即高癫痫发作负荷也可能触发促进神经炎症消退和脑修复的特殊促消退介质的积累。因此，本研究旨在探讨在德雷维特综合征的Scn1a小鼠模型中，高癫痫发作负荷是否会增加海马中各种特殊促消退介质的浓度。
对出生后第21天（P21）的Scn1a小鼠进行一次热诱导癫痫发作，以诱导高癫痫发作负荷。在P24时，对有高癫痫发作负荷的预处理Scn1a小鼠、未预处理的幼稚Scn1a小鼠和野生型（WT）小鼠实施安乐死，并收集海马组织，使用液相色谱质谱法分析各种特殊促消退介质。
有高癫痫发作负荷的Scn1a小鼠海马中促炎白三烯B4和E4的浓度增加。此外，高癫痫发作负荷增加了海马中各种特殊促消退介质的浓度，包括maresins（maresin1）、D系列消退素（RVD1和RVD4）和保护素（PCTR1）。为了进一步表征这些变化，我们测定了脂氧合酶基因的mRNA表达，因为这些合成酶在各类特殊促消退介质中是常见的。然而，海马中Alox5、Alox12和Alox15的表达不受高癫痫发作负荷的影响。
我们首次报道，高癫痫发作负荷会增加Scn1a小鼠海马中各种特殊促消退介质的浓度。这为未来的研究提供了一个平台，以探讨是否可以利用这些介质的调节作用来减少癫痫发作，并促进难治性癫痫综合征中的脑修复。
