ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms.
ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms.
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DOI：
10.1038/s41598-018-24013-x
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发表时间：
2018-04-10
影响因子：
4.6
通讯作者：
Velíšek L
中科院分区：
文献类型：
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作者：
Iacobaş DA;Chachua T;Iacobaş S;Benson MJ;Borges K;Velíšková J;Velíšek L
我们分析了20只雄性和20只雌性大鼠下丘脑弓状核（ARC）的基因表达，以确定婴儿痉挛（IS）相关的神经传递和恢复的转录组学改变。大鼠出生前暴露于倍他米松或生理盐水，随后出生后重复暴露于NMDA触发的IS。用ACTH、PMX 53或盐水治疗痉挛大鼠。由于IS的一线治疗ACTH具有不一致的疗效和潜在的严重副作用，PMX 53，一种有效的补体C5ar 1拮抗剂，被建议作为一种治疗替代方案，考虑到其在其他癫痫模型中的作用。除了标准统计检验外，还使用了考虑所有基因且不受任意截止值影响的新措施来量化多巴胺能、GABA能、胆碱能、多巴胺能和多巴胺能途径的调节和恢复。尽管IS改变了两种性别中约30%的ARC基因的表达，但如加权途径调节测量所示，雄性中的转录组效应比雌性中的转录组效应严重3倍。根据路径恢复效率测量，这两种治疗均显着将ARC神经传递转录组恢复到非IS状态，其中PMX 53表现稍好，这表明这些治疗可能会减少通常与IS相关的自闭症特征。
We profiled the gene expression in the hypothalamic arcuate nuclei (ARC) of 20 male and 20 female rats to determine the infantile spasms (IS) related transcriptomic alteration of neurotransmission and recovery following two treatments. Rats were prenatally exposed to betamethasone or saline followed by repeated postnatal subjection to NMDA-triggered IS. Rats with spasms were treated with ACTH, PMX53 or saline. Since ACTH, the first line treatment for IS, has inconsistent efficacy and potential harsh side effects, PMX53, a potent complement C5ar1 antagonist, was suggested as a therapeutic alternative given its effects in other epilepsy models. Novel measures that consider all genes and are not affected by arbitrary cut-offs were used, in addition to standard statistical tests, to quantify regulation and recovery of glutamatergic, GABAergic, cholinergic, dopaminergic and serotonergic pathways. Although IS alters expression of ~30% of the ARC genes in both sexes the transcriptomic effects are 3× more severe in males than their female counterparts, as indicated by the Weighted Pathway Regulation measure. Both treatments significantly restored the ARC neurotransmission transcriptome to the non-IS condition with PMX53 performing slightly better, as measured by the Pathway Restoration Efficiency, suggesting these treatments may reduce autistic traits often associated with IS.
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影响因子：
5.6
作者：
Benson, Melissa J.;Manzanero, Silvia;Borges, Karin
通讯作者：
Borges, Karin
影响因子：
2.4
作者：
Iacobas, Dumitru A.;Suadicani, Sylvia O.;Scemes, Eliana
通讯作者：
Scemes, Eliana
影响因子：
5.8
作者：
Iacobas, Dumitru A.;Iacobas, Sanda;Spray, David C.
通讯作者：
Spray, David C.
乳头状和甲状腺甲状腺癌的基因主调节剂。
影响因子：
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作者：
Iacobas DA;Tuli NY;Iacobas S;Rasamny JK;Moscatello A;Geliebter J;Tiwari RK
通讯作者：
Tiwari RK
影响因子：
64.8
作者：
通讯作者：
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