Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1-13 C]pyruvate.
Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1-13 C]pyruvate.
复制标题
使用超极化[1-13 C]丙酮酸盐对急性创伤性脑损伤中线粒体功能障碍进行纵向评估。
DOI：
10.1002/mrm.29794
复制
发表时间：
2023
影响因子：
3.3
通讯作者：
Park,JaeMo
中科院分区：
文献类型：
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作者：
Hackett,EdwardP;Chen,Jun;Ingle,Laura;AlNemri,Sarah;Barshikar,Surendra;daCunhaPinho,Marco;Plautz,ErikJ;Bartnik-Olson,BrendaL;Park,JaeMo
[13C]超极化[1‐13C]丙酮酸通过关键调节酶丙酮酸脱氢酶形成碳酸氢盐，代表了丙酮酸的大脑氧化和线粒体功能的完整性。本研究通过纵向监测超极化[1‐13C]丙酮酸产生的[13C]碳酸氢盐，来描述啮齿动物急性创伤性脑损伤（TBI）继发性损伤期间脑线粒体代谢的年代学特征。方法将Wistar小鼠随机分为控制性皮质冲击组（CCI,n= 31）和假手术组（n= 22）。17只CCI大鼠和9只假大鼠纵向接受了a1H/13C -整合MR方案，包括在术后0（2小时）、1、2、5和10天大量注射超极化[1 - 13C]丙酮酸。分别用CCI大鼠和假大鼠进行组织学验证和酶分析。结果除了乳酸升高外，我们观察到损伤部位的碳酸氢盐产量显著减少。与T2加权MRI上立即出现的高强度不同，损伤区域和对侧大脑之间的碳酸氢盐信号对比在损伤后24小时达到峰值，然后在第10天完全恢复到正常水平。一组TBI大鼠在损伤后表现出对侧正常脑区碳酸氢盐明显增加。本研究表明，通过检测超极化[1‐13C]丙酮酸产生的[13C]碳酸氢盐可以监测急性TBI中发生的异常线粒体代谢，这表明[13C]碳酸氢盐是继发性损伤过程的敏感体内生物标志物。
Purpose[13C]Bicarbonate formation from hyperpolarized [1‐13C]pyruvate via pyruvate dehydrogenase, a key regulatory enzyme, represents the cerebral oxidation of pyruvate and the integrity of mitochondrial function. The present study is to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute traumatic brain injury (TBI) by longitudinally monitoring [13C]bicarbonate production from hyperpolarized [1‐13C]pyruvate in rodents.MethodsMale Wistar rats were randomly assigned to undergo a controlled‐cortical impact (CCI,n= 31) or sham surgery (n= 22). Seventeen of the CCI and 9 of the sham rats longitudinally underwent a1H/13C‐integrated MR protocol that includes a bolus injection of hyperpolarized [1‐13C]pyruvate at 0 (2 h), 1, 2, 5, and 10 days post‐surgery. Separate CCI and sham rats were used for histological validation and enzyme assays.ResultsIn addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T2‐weighted MRI, the contrast of bicarbonate signals between the injured region and the contralateral brain peaked at 24 h post‐injury, then fully recovered to the normal level at day 10. A subset of TBI rats demonstrated markedly increased bicarbonate in normal‐appearing contralateral brain regions post‐injury.ConclusionThis study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [13C]bicarbonate production from hyperpolarized [1‐13C]pyruvate, suggesting that [13C]bicarbonate is a sensitive in‐vivo biomarker of the secondary injury processes.