Abstract
Complex alterations in cerebral energetic metabolism arise after traumatic brain injury (TBI). To date, methods allowing for metabolic evaluation are highly invasive, limiting our understanding of metabolic impairments associated with TBI pathogenesis. We investigated whether 13C MRSI of hyperpolarized (HP) [1-13C] pyruvate, a non-invasive metabolic imaging method, could detect metabolic changes in controlled cortical injury (CCI) mice (n = 57). Our results show that HP [1-13C] lactate-to-pyruvate ratios were increased in the injured cortex at acute (12/24 hours) and sub-acute (7 days) time points after injury, in line with decreased pyruvate dehydrogenase (PDH) activity, suggesting impairment of the oxidative phosphorylation pathway. We then used the colony-stimulating factor-1 receptor inhibitor PLX5622 to deplete brain resident microglia prior to and after CCI, in order to confirm that modulations of HP [1-13C] lactate-to-pyruvate ratios were linked to microglial activation. Despite CCI, the HP [1-13C] lactate-to-pyruvate ratio at the injury cortex of microglia-depleted animals at 7 days post-injury remained unchanged compared to contralateral hemisphere, and PDH activity was not affected. Altogether, our results demonstrate that HP [1-13C] pyruvate has great potential for in vivo non-invasive detection of cerebral metabolism post-TBI, providing a new tool to monitor the effect of therapies targeting microglia/macrophages activation after TBI.
Highlights
Traumatic brain injury (TBI) is a complex and heterogeneous brain pathology characterized by various degrees of tissue damage, hemorrhages and edema caused by the primary mechanical insult and subsequent secondary injury responses such as neuroinflammation[1,2,3,4,5,6]
To further investigate the origin of HP [1-13C] lactate-to-pyruvate ratio alterations following injury, we evaluated the activity of two keys enzymes that control the fate of pyruvate, namely lactate dehydrogenase (LDH), which converts pyruvate into lactate, and pyruvate dehydrogenase (PDH) which enables the entry of pyruvate into the TCA cycle
We evaluated for the first time the potential of an innovative neuroimaging method, HP 13C MRSI, to monitor longitudinal changes in energetic metabolism in a cortical impact (CCI) mouse model of traumatic brain injury (TBI)
Summary
Traumatic brain injury (TBI) is a complex and heterogeneous brain pathology characterized by various degrees of tissue damage, hemorrhages and edema caused by the primary mechanical insult and subsequent secondary injury responses such as neuroinflammation[1,2,3,4,5,6]. Evaluation of cerebral metabolism usually relies on invasive methods, such as microdialysis, for direct assessment of brain metabolites or indirect measures of arterio-venous metabolite concentrations[11,12] These methods have demonstrated that injured tissue is characterized by high lactate level and a high lactate-to-pyruvate ratio[13,14,15]. Over the past decade, hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) has emerged as a clinically translatable neuroimaging method of high potential This new imaging strategy allows monitoring of enzymatic reactions in vivo in real-time after injection of so-called hyperpolarized (HP) 13C-labeled www.nature.com/scientificreports/. DeVience et al have recently shown that HP 13C MRSI can detect altered HP [1-13C] pyruvate-to-lactate conversion in a rat model of TBI, at an acute time point (4 hours) following injury[27]. At these acute and sub acute time points, we observed a decreased activity of pyruvate dehydrogenase (PDH), the enzyme which converts pyruvate into Acetyl-CoA, providing a likely mechanism for the observed increased HP [1-13C] lactate production
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