Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Magn Reson Med. 2023 Dec;90(6):2432-2442. doi: 10.1002/mrm.29794. Epub 2023 Jul 10.
[ C]Bicarbonate formation from hyperpolarized [1- C]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 [ C]bicarbonate production from hyperpolarized [1- C]pyruvate in rodents.
Male 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 a H/ C-integrated MR protocol that includes a bolus injection of hyperpolarized [1- C]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.
In addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T -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.
This study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [ C]bicarbonate production from hyperpolarized [1- C]pyruvate, suggesting that [ C]bicarbonate is a sensitive in-vivo biomarker of the secondary injury processes.
[C]通过丙酮酸脱氢酶（一种关键调节酶）从 1-[C]丙酮酸中形成重氢碳酸盐，代表了丙酮酸的脑氧化和线粒体功能的完整性。本研究旨在通过纵向监测急性创伤性脑损伤（TBI）相关继发性损伤期间脑线粒体代谢的时间进程，来对其进行特征描述。该研究使用啮齿动物模型，对其进行了 [1-[C]丙酮酸的 H/C 整合性磁共振（MR）方案的纵向监测，即在术后 0（2 小时）、1、2、5 和 10 天进行重氢碳酸盐的产生。
雄性 Wistar 大鼠被随机分配接受皮质控制冲击（CCI，n=31）或假手术（n=22）。17 只 CCI 大鼠和 9 只假手术大鼠接受了 H/C 整合性 MR 方案，其中包括在术后 0（2 小时）、1、2、5 和 10 天进行 [1-[C]丙酮酸的重氢碳酸盐产生。单独的 CCI 和假手术大鼠用于组织学验证和酶测定。
除了升高的乳酸，我们还观察到损伤部位的重氢碳酸盐产生明显减少。与 T1 加权 MRI 上立即出现的高信号不同，损伤区域与对侧大脑之间的重氢碳酸盐信号对比度在损伤后 24 小时达到峰值，然后在第 10 天完全恢复到正常水平。一部分 TBI 大鼠在损伤后表现出正常的对侧脑区域中重氢碳酸盐明显增加。
这项研究表明，通过检测 1-[C]丙酮酸重氢碳酸盐的产生，急性 TBI 中发生的异常线粒体代谢可以得到监测，这表明重氢碳酸盐是继发性损伤过程的敏感体内生物标志物。
