A high seizure burden increases several prostaglandin species in the hippocampus of a Scn1a+/- mouse model of Dravet syndrome

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Cilla Zhou , Vaishali Satpute , Ka Lai Yip , Lyndsey L. Anderson , Nicole Hawkins , Jennifer Kearney , Jonathon C. Arnold
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Abstract

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus. Moreover, we examined whether a high seizure burden influences classical inflammatory mediators in this brain region. Scn1a+/- mice with a high seizure burden induced by thermal priming displayed a localised reduction in microglial cell density in the granule cell layer and subgranular zone of the dentate gyrus, regions important to postnatal neurogenesis. However, microglial cell number and morphology remained unchanged in other hippocampal subfields. The high seizure burden in Scn1a+/- mice did not affect hippocampal mRNA expression of classical inflammatory mediators such as interleukin 1β and tumour necrosis factor α, but increased cyclooxygenase 2 (COX-2) expression. We then quantified hippocampal levels of prostanoids that arise from COX-2 mediated metabolism of fatty acids and found that Scn1a+/- mice with a high seizure burden displayed increased hippocampal concentrations of numerous prostaglandins, notably PGF, PGE2, PGD2, and 6-K-PGF1A, compared to Scn1a+/- mice with a low seizure burden. In conclusion, a high seizure burden increased hippocampal concentrations of various prostaglandin mediators in a mouse model of Dravet syndrome. Future studies could interrogate the prostaglandin pathways to further better understand their role in the pathophysiology of Dravet syndrome.

高癫痫发作负担会增加Scn1a+/-德雷维综合征小鼠模型海马中的几种前列腺素种类
德雷维综合征是一种难治性癫痫,发作量大,对目前的抗癫痫药物有抗药性。有证据表明,神经炎症在癫痫和癫痫发作中起着一定的作用,但很少有研究专门研究在癫痫发作负荷较高的条件下,神经炎症在德雷维综合征中的作用。在这里,我们使用一种已建立的遗传性小鼠模型(Scn1a+/- 小鼠)来研究较高的癫痫发作负担是否会影响海马中小胶质细胞的数量和形态。此外,我们还研究了较高的癫痫发作负担是否会影响该脑区的经典炎症介质。通过热引物诱导的高癫痫发作负担的 Scn1a+/- 小鼠显示出齿状回颗粒细胞层和粒下区小胶质细胞密度的局部降低,而这些区域对出生后的神经发生非常重要。然而,其他海马亚区的小胶质细胞数量和形态保持不变。Scn1a+/-小鼠的高癫痫负荷并不影响海马经典炎症介质(如白细胞介素1β和肿瘤坏死因子α)的mRNA表达,但会增加环氧化酶2(COX-2)的表达。我们随后量化了海马中由 COX-2 介导的脂肪酸代谢所产生的前列腺素水平,发现与癫痫发作负担较轻的 Scn1a+/- 小鼠相比,癫痫发作负担较重的 Scn1a+/- 小鼠海马中多种前列腺素的浓度增加,尤其是 PGF2α、PGE2、PGD2 和 6-K-PGF1A。总之,高癫痫发作负担增加了小鼠海马中各种前列腺素介质的浓度。未来的研究可以探讨前列腺素通路,以进一步更好地了解它们在德雷维综合征病理生理学中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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