丙戊酸治疗外伤性脑损伤后可挽救损伤组织。
Valproic acid treatment rescues injured tissues after traumatic brain injury.
机构信息
From the Department of Surgery (B.E.B., L.P., A.I., A.A.S., A.Z.S., R.L.O., G.K.W., M.T.K., A.M.W., H.B.A.), Department of Biological Chemistry (H.A.R.), and Department of Clinical Pharmacy (M.P.P.), University of Michigan, Ann Arbor, Michigan.
出版信息
J Trauma Acute Care Surg. 2020 Dec;89(6):1156-1165. doi: 10.1097/TA.0000000000002918.
BACKGROUND
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 has 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 prosurvival pathways.
METHODS
Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 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 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.
RESULTS
Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 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.
CONCLUSION
Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival 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.
背景
目前尚无专门用于紧急治疗创伤性脑损伤（TBI）患者的神经保护剂。高剂量丙戊酸（VPA）是一种组蛋白去乙酰化酶抑制剂，已在 TBI 合并失血性休克模型中显示出具有细胞保护潜力，但尚未在单独的 TBI 模型中进行测试。我们假设，在单独的 TBI 后给予 VPA，将穿透受伤的大脑，减轻病变大小，并激活生存途径。
方法
通过皮质撞击使约克夏猪发生严重的 TBI。1 小时后，动物被随机分为 VPA 治疗组（150mg/kg 静脉内输注 1 小时；n=4）或对照组（生理盐水载体；n=4）。伤后 7 小时，处死动物并测量脑损伤大小。使用质谱成像来可视化和定量 VPA 在脑组织中的分布。连续采集血清样本，检测关键生物标志物，并进行蛋白质组和途径分析。
结果
VPA 治疗组（3837±948mm）的脑损伤面积比对照组（1900±614mm）小 50%（p=0.01）。通过质谱成像，血管周围区的 VPA 浓度比血管内皮区高 8 倍，并且它很容易穿透受伤的脑组织。VPA 治疗组的血清神经胶质纤维酸性蛋白明显低于对照组（p<0.05）。大脑中有超过 500 种蛋白质表达差异，途径分析表明，VPA 影响了 TBI 反应的关键调节剂，包括钙信号通路、线粒体代谢和生物合成机制。
结论
丙戊酸穿透受伤的脑组织，发挥神经保护和生存作用，导致单独 TBI 后的脑损伤面积显著减小。血清生物标志物的水平反映了这些变化，这可能对监测临床试验中 TBI 患者的反应有用。
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