Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures.
Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures.
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DOI：
10.1016/j.nbd.2022.105873
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发表时间：
2022-11
影响因子：
6.1
通讯作者：
Hernan, Amanda E.
中科院分区：
文献类型：
--
作者：
Brabec, Jeffrey L.;Ouardouz, Mohamed;Mahoney, J. Matthew;Scott, Rod C.;Hernan, Amanda E.
早期癫痫发作（ELS）与持续的认知缺陷（如ADHD和记忆障碍）有关。这些合并症对患者的生活质量有显著的负面影响。改善认知结果的疗法具有改善患者生活质量的巨大潜力。我们以前在大鼠氟乙烯诱导模型中的工作表明，在癫痫发作诱导时给予促肾上腺皮质激素（ACTH）可改善动物的学习和记忆，尽管对癫痫发作潜伏期或持续时间没有影响。地塞米松（Dex），一种皮质类固醇，对学习和记忆没有同样的积极作用，甚至被证明会加重颞叶癫痫大鼠模型的损伤。我们假设ACTH通过基因表达的有益变化对认知结果产生积极影响，并提出在癫痫发作诱导时给予ACTH将使对照动物大脑中的基因表达恢复到正常表达模式，而Dex则不会。将26只Sprague-Dawley大鼠随机分为溶媒对照组、ACTH-ELS组、Dex-ELS组和溶媒ELS组。从P5至P14，对大鼠幼仔进行60次氟乙酸癫痫发作。诱导癫痫发作后，取出大脑，解剖海马和PFC，提取RNA并测序，使用广义估计方程进行差异表达分析。差异表达分析表明，促肾上腺皮质激素推动大脑中的基因表达回到一个更正常的表达状态，通过丰富的途径参与支持稳态平衡和下调途径，可能有助于兴奋性毒性细胞损伤后ELS。
Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients’ quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not. Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle- ELS. Rat pups were subjected to 60 flurothyl seizures from P5 to P14. After seizure induction, brains were removed and the hippocampus and PFC were dissected, RNA was extracted and sequenced, and differential expression analysis was performed using generalized estimating equations. Differential expression analysis showed that ACTH pushes gene expression in the brain back to a more normal state of expression through enrichment of pathways involved in supporting homeostatic balance and down-regulating pathways that might contribute to excitotoxic cell-damage post-ELS.
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影响因子：
4.2
作者：
Giuliani, Daniela;Bitto, Alessandra;Guarini, Salvatore
通讯作者：
Guarini, Salvatore
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.1
作者：
Duffy BA;Chun KP;Ma D;Lythgoe MF;Scott RC
通讯作者：
Scott RC
癫痫发作后，成年海马神经元整合过程中突触性质的改变。
影响因子：
3.7
作者：
Jackson J;Chugh D;Nilsson P;Wood J;Carlström K;Lindvall O;Ekdahl CT
通讯作者：
Ekdahl CT
影响因子：
3.4
作者：
Massey AT;Lerner DK;Holmes GL;Scott RC;Hernan AE
通讯作者：
Hernan AE