A Metabolomics Study of Hypoxia Ischemia during Mouse Brain Development Using Hyperpolarized ¹³C

Abstract

Background: Hyperpolarized 13 C spectroscopic magnetic resonance spectroscopy (MRS) is an advanced imaging tool that may provide important real-time information about brain metabolism. Methods: Mice underwent unilateral hypoxia-ischemia (HI) on postnatal day (P)10. Injured and sham mice were scanned at P10, P17, and P31. We used hyperpolarized 13 C MRS to investigate the metabolic exchange of pyruvate to lactate in real time during brain development following HI. 13 C-1-labeled pyruvate was hyperpolarized and injected into the tail vein through a tail-vein catheter. Chemical-shift imaging was performed to acquire spectral-spatial information of the metabolites in the brain. A voxel placed on each of the injured and contralateral hemispheres was chosen for comparison. The difference in pyruvate delivery and lactate to pyruvate ratio was calculated for each of the voxels at each time point. The normalized lactate level of the injured hemisphere was also calculated for each mouse at each of the scanning time points. Results: There was a significant reduction in pyruvate delivery and a higher lactate to pyruvate ratio in the ipsilateral (HI) hemisphere at P10. The differences decreased at P17 and disappeared at P31. The normalized lactate level in the injured hemisphere increased from P10 to P31 in both sham and HI mice without brain injury. Conclusion: We describe a method for detecting and monitoring the evolution of HI injury during brain maturation which could prove to be an excellent biomarker of injury.

LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion—An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-13C]Pyruvate

“…In another study, the authors used a model of endothelin-1 injection (a potent vasoconstrictor) [ 42 ] and found that the signals of hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate were increased in the ischemic penumbra region 18 h following the induced stroke, while the [1- 13 C]lactate/[1- 13 C]pyruvate signal ratio remained unchanged. Another study examined the effect of ischemia on the developing mouse brain [ 52 ], and found that the hyperpolarized [1- 13 C]lactate to [1- 13 C]pyruvate signal ratio was higher in the injured hemisphere compared to the control one 2–5 h following the insult, and returned to baseline levels 20 days following the insult. It is important to note that in addition to the use of other model systems than the set-up used here (such as in vivo vs. ex vivo and different time scales), these previous studies did not determine enzyme activity.…”

NMR metabolomic and microarray-based transcriptomic data integration identifies unique molecular signatures of hypersensitivity pneumonitis

“…An increase in lactate and downregulation of pyruvate observed in HP patients is suggestive of hypoxic condition in these cases, which is in good agreement with other studies. 48,49 Nonetheless, our observations should be interpreted with caution since additional studies are needed to establish the imbalance between lactate and pyruvate levels. We also observed an abundance of proline in BALF and its downregulation in serum and EBC of HP subjects.…”

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia

“…Since no exogenous lactate was administered in our experiments, the observed effect must be due to endogenous lactate or possible baseline receptor activity. Indeed, a similar HI mouse model showed a lactate rise in the ipsilateral hemisphere ( Mikrogeorgiou et al, 2020 ). Moreover, the lactate level rises in neonatal humans and piglets after a hypoxic-ischemic episode ( Roelants-Van Rijn et al, 2001 ; Wu et al, 2018a ; Zheng and Wang, 2017 ).…”