Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury.
Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury.
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DOI：
10.1097/ta.0000000000001765
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
Alam HB
中科院分区：
文献类型：
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作者：
Nikolian VC;Dennahy IS;Higgins GA;Williams AM;Weykamp M;Georgoff PE;Eidy H;Ghandour MH;Chang P;Alam HB
丙戊酸 (VPA) 的早期治疗已在创伤性脑损伤 (TBI) 的临床前模型中显示出益处，包括缩小脑病灶大小、减少水肿、减少神经功能障碍和更快恢复。这些有利结果背后的机制尚不完全清楚。我们假设 VPA 治疗会上调与细胞存活和增殖有关的基因，并下调与细胞死亡和炎症反应相关的基因。对 10 只雌性猪进行 TBI 和失血性休克治疗。他们被分配到两组 (n=5)：生理盐水组（NS；3 倍流血量）或 NS + VPA (150 mg/kg)。观察6小时后，采集脑组织以评估病变大小和水肿。脑组织被处理用于 RNA 测序。进行基因集富集和通路分析以确定损伤后的差异基因表达模式。使用 VPA 治疗的动物的脑损伤大小减少了 46%，同侧脑水肿减少了 57%。 VPA显着上调涉及神经系统形态、神经元发育和神经元数量的基因。 VPA 治疗下调与细胞凋亡、神经胶质细胞增殖和神经上皮细胞分化相关的途径。 Ingenuity Pathway Analysis 确定 VPA 是激活转录的顶级上游调节因子，支持其作为这些转录变化的直接原因。主转录调节因子 NEUROD1 也显着上调，表明 VPA 可能诱导额外的转录因子。 VPA 的施用可以缩小脑损伤的大小，减少脑水肿，并在 6 小时内诱导受损脑的转录组发生显着变化。差异表达模式与 VPA 治疗的神经源性和促生存作用一致。
Early treatment with valproic acid (VPA) has demonstrated benefit in pre-clinical models of traumatic brain injury (TBI), including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response. Ten female swine were subjected to a protocol of TBI and hemorrhagic shock. They were assigned to two groups (n=5): normal saline (NS; 3X volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury. Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. VPA significantly up-regulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors. Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and pro-survival effects of VPA treatment.