Valproic acid treatment rescues injured tissues after traumatic brain injury.
Valproic acid treatment rescues injured tissues after traumatic brain injury.
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DOI：
10.1097/ta.0000000000002918
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Alam HB
中科院分区：
文献类型：
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作者：
Biesterveld BE;Pumiglia L;Iancu A;Shamshad AA;Remmer HA;Siddiqui AZ;O'Connell RL;Wakam GK;Kemp MT;Williams AM;Pai MP;Alam HB
目前还没有专门的神经保护药物被批准用于紧急治疗创伤性脑损伤 (TBI) 患者。组蛋白脱乙酰酶抑制剂高剂量丙戊酸 (VPA) 已被证明在合并 TBI 和失血性休克模型中具有细胞保护潜力，但尚未在孤立的 TBI 模型中进行测试。我们假设，在孤立性 TBI 后施用 VPA，将穿透受伤的大脑，缩小病变范围，并激活促生存途径。约克郡猪因皮质撞击而遭受严重的创伤性脑损伤。一小时后，动物被随机分为 VPA 治疗组（1 小时内静脉注射 150 mg/kg；n=4）或对照组（盐水载体；n=4）。受伤后七小时，处死动物，并测量脑损伤大小。质谱 (MS) 成像用于可视化和定量 VPA 的脑组织分布。对连续血清样本进行关键生物标志物分析，并进行蛋白质组学和通路分析。与对照组 (1900±614 mm3) 相比，VPA 治疗动物 (3837±948 mm3) 的脑损伤尺寸小 50% (p=0.01)。 MS 成像显示，内皮区域的 VPA 浓度比血管周围区域高 8 倍，并且很容易穿透受损的脑组织。与对照动物相比，VPA 治疗组的血清胶质原纤维酸性蛋白显着降低（p<0.05）。超过 500 种蛋白质在大脑中差异表达，通路分析显示 VPA 影响 TBI 反应的关键调节因子，包括钙信号通路、线粒体代谢和生物合成机制。 VPA 穿透受伤的脑组织，发挥神经保护和促生存作用，导致孤立性 TBI 后脑损伤大小显着减小。血清生物标志物的水平反映了这些变化，这可能有助于在临床研究期间监测 TBI 患者的反应。不适用；基础科学。
No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate pro-survival pathways. Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously over 1 hour; n=4) or control (saline vehicle; n=4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry (MS) imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers, and subjected to proteomic and pathway analysis. Brain lesion size was 50% smaller (p=0.01) in the VPA treated animals (3837±948 mm3) compared to the controls (1900±614 mm3). Endothelial regions had 8-fold higher VPA concentrations than perivascular regions by MS-imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared to the control animals (p<0.05). Over 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism and biosynthetic machinery. VPA penetrates injured brain tissues, and exerts neuroprotective and pro-survival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies. Not applicable; basic science.