Tracking Hyperpolarized [1-¹³C] Pyruvate and [1-¹³C] L-Lactate Metabolism in the Healthy and Post-Stroke Mouse Brain

Tracking hyperpolarized (HP) ¹³C labeling from either [1-¹³C] pyruvate or [1-¹³C] lactate is a useful tool to assess intermediary metabolism in vivo, which has already been translated from preclinical to clinical research. HP [1-¹³C] pyruvate and [1-¹³C] lactate provide complementary views on the same metabolic pathway, and both have been tested as potential neuroprotective agents in the context of acute brain injuries, with more convincing evidence for a beneficial effect of lactate. Our aim here was to investigate and compare HP [1-¹³C] pyruvate and [1-¹³C] lactate performance as metabolic contrast agents in the brains of healthy mice and mice subjected to middle cerebral artery occlusion, a model of ischemic stroke. We analyzed the metabolite ratios and quantified the real-time apparent kinetic rates of their cerebral metabolism. We found that the cerebral metabolism of both HP [1-¹³C] pyruvate and HP [1-¹³C] lactate showed significant alterations after transient cerebral ischemia in mice, reflecting the damage as well as the metabolic reprogramming set in motion to meet the energetic demands in the acute phase of stroke. There was a significant decrease in metabolite ratios (cLPR, cAPR for pyruvate bolus and cPLR, cALR for lactate bolus) and kinetic rates (ck_PL for pyruvate bolus and ck_LP for lactate bolus). These values progressively decreased from sham to 1 h and 2 h after reperfusion measurements. Overall, while pyruvate is better established as an imaging probe, and lactate appears advantageous on the therapeutic side, both bring information to interrogate brain metabolism in physiological and pathophysiological conditions in real time. This study prepares the ground for further investigation to fully exploit the potential of HP metabolic contrasts for stroke theranostics.